NEUROSCIENCE CENTER
ANNUAL REPORT
2008
Neuroscience Center Annual Report 2008
Editors
Layout
Photos
Anna Mattila and Minna Maunula
Anita Tienhaara
Veikko Somerpuro and Eero Roine
Neuroscience Center
P.O. Box 56, Viikinkaari 4
FI-00014 University of Helsinki, Finland
Phone +358 9 1911
Fax +358 9 191 57620
www.helsinki.fi/neurosci
Contents
Preface
4
Research Highlights
6
Organization of the Neuroscience Center
10
Research Groups
11
Adjunct Professors
32
Teaching at the Neuroscience Center
33
Core Facilities
Mouse Behavioural Unit
39
Mouse Transgenic Unit
40
Neuronal Cell Culture Unit
41
Zebrafish Unit
42
Neuroscience Center Research and Centres of Excellence
Finnish Centre of Excellence in Complex Disease Genetics
43
Finnish Centre of Excellence in Molecular and Integrative
Neuroscience Research
43
Commercialization and Spin-Off Activities: Founding of Hermo Pharma Ltd.
44
Administration
46
Publications
47
Theses
50
Finances
51
Staff
52
Personnel
53
ANNUAL REPORT 2008
4
Preface
Heikki Rauvala
Director of the Neuroscience Center
Changes are currently underway in the university
structures in Finland. Provided that the Parliament passes
a new law in spring 2009, the autonomy of universities
will increase with regard to public administration. One
major change will be that persons selected from outside
the university will form the majority in the government
of the new university. This will create a situation where
major changes are likely to occur in the research and
teaching profiles of universities.
In 2008, the University of Helsinki started to prepare
for the new university structure. In particular, the size of
departments is being increased, with the aim that these
departments would form the units to which resources
are allocated and would be responsible for the finances
of their research and teaching areas. The department
directors will have more responsibilities than before,
especially concerning department finances.
Considering the departmental size limitations
defined by the Central Administration of the University,
the Neuroscience Center (NC) appears sufficiently large to
act as an independent unit. Fusion of the NC to a faculty
or some other institution is not currently foreseeable.
However, neuroscience research is still rather fragmented
in the capital area, which calls for closer cooperation
between the different units. Possibilities for common
programs with the newly formed Aalto University and
the faculties of the University of Helsinki are currently
being explored. Whether this will lead to changes in how
neuroscience research is organized in the capital area
remains to be seen.
As of the beginning of 2009, the NC has 12
research groups and a personnel of 130. The proportion
of foreigners on staff is higher than in previous years; for
researchers it was 43% in 2008.
Based on the recommendation by the Scientific
Advisory Board (SAB), Professor Kai Kaila started a 5-year
period as Research Director at the beginning of 2008.
Professor Kaila´s laboratory is a joint effort between the
NC and the Department of Biosciences and Environmental
Sciences in the Faculty of Biosciences. Professor Kaila´s
work extends from molecular/cellular to systems-level
studies in basic neuroscience. Professor Kaila’s group has
been highly innovative in producing clinical applications
based on basic research, an important additional activity
for the NC.
ANNUAL REPORT 2008
Based on the evaluation by the SAB, all groups
initially selected to the NC have entered their second
5-year period within the NC at the beginning of 2008.
The SAB has strongly recommended continuing the
system whereby a few excellent researchers are selected
as Adjunct Professors to work on selected topics at their
home institutions, but receive part of their funding from
the NC. Of the Adjunct Professors, Adrian Goldman
(University of Helsinki) and Heikki Tanila (University of
Kuopio) were selected to continue for another 3-year
period. Professors Juha Kere (University of Helsinki and
Karolinska Institute) and Pekka Lappalainen (University of
Helsinki) have started as new Adjunct Professors at the
beginning of 2008.
The NC aims at recruiting young talented scientists
to build their own research groups. According to this
strategy, Drs. Henri Huttunen and Pirta Hotulainen
have joined the crew in 2008. Dr. Huttunen investigates
molecular mechanisms of neurodegeneration, particularly
pathogenetic mechanisms of Alzheimer´s disease. Dr.
Hotulainen researches developmental mechanisms of
synaptic structures. The new groups will strenghten
the profile of the NC in molecular/cellular neuroscience
and in research of basic mechanisms of nervous system
diseases.
The Centre of Excellence in Molecular and Integrative
Neuroscience Research started at the beginning of 2008
and connects research at the NC with that of the Institute
of Biotechnology and the Department of Biosciences
and Environmental Sciences. Groups led by Airaksinen,
Castrén, Kaila, and Rauvala belong to the seven research
groups forming this Centre of Excellence. In addition, Dr.
Lehesjoki´s group is one of the seven research groups
forming the Centre of Excellence in Complex Disease
Genetics.
A few research highlights have been selected to
profile current NC research in the Annual Report 2008.
Matti Airaksinen writes about new roles and molecular
forms of K-Cl cotransporter, an important regulator
of excitation/inhibition balance in the brain. Eero
Castrén´s group studies the roles of neurotrophins and
antidepressants in brain plasticity. The second highlight
deals with these studies and their potential to harness
plasticity mechanisms to correct amblyopia in adults. The
third highlight by Kai Kaila discusses endogenous activity
of the immature brain and EEG developments to monitor
such activity in human preterm neonates. These studies
illustrate the importance of basic neuroscience in the
development of clinical applications. The fourth highlight
by Matias Palva deals with computational approaches
to shed light on rhythmic interactions of different
brain areas. The systems-level approach by the group is
expected to be valuable for other research projects of
the NC, and is in fact currently applied in brain plasticity
studies that previously have been mainly carried out at
the molecular/cellular level.
From its establishment in 2002, the NC has
been developing a systematic teaching program of
neuroscience. This teaching program forms the basis
of the international Master´s Degree Program in
Neuroscience – MNEURO – which was initiated in
cooperation with the Faculty of Biosciences in fall 2008.
The program includes the research areas covered by the
NC: molecular and cellular neuroscience, developmental
neuroscience, neuronal disorders, systems neuroscience,
and neurobiophysics. The first admission of students
was successfully carried out in fall 2008, and the second
admission is currently underway.
Neuroscience research at the University of Helsinki
has generated top-level scientific inventions with
marked commercial potential. To facilitate practical
applications of such findings, the NC has launched a
commercialization program in collaboration with the
Institute of Biotechnology and the Finnish Funding
Agency for Technology and Innovation (TEKES). As a
result of this activity, Hermo Pharma Limited was founded
in 2008. The company focuses on novel ideas to treat
neurodegenerative diseases and to exploit neuronal
plasticity mechanisms in therapeutic strategies. The next
few years will reveal whether this spin-off activity from
basic neuroscience research is successful.
In conclusion, I would like to thank everyone at the
NC, our collaborators, and the members of the Boards
for making the Center an inspiring and pleasant place
to work. I am very much looking forward to the new
possibilities and challenges that will emerge from the
restructuring of the university in the coming years.
5
ANNUAL REPORT 2008
Research Highlights
New roles for the neuronal K-Cl
cotransporter
Matti Airaksinen
Synchronized control of excitatory and inhibitory synapse
maturation is crucial for normal brain wiring. The KCC2
cotransporter, working as a Cl- pump, is critical for fast
hyperpolarizing GABAA and glycine receptor-mediated
inhibition (Blaesse et al. 2009). Consistent with this,
neurons from mice with reduced KCC2 protein levels lack
hyperpolarizing GABA inhibition and are hyperexcitable.
However, the central role of shunting-type inhibition
in controlling neuronal excitability is underscored by
the relatively mild behavioral phenotype as well as by
unaltered basic excitatory transmission in these mice
(Riekki et al. 2008). The KCC2 gene generates two
isoforms with different N-termini (Figure, panel a).
Upregulation of the KCC2b isoform is responsible for
the postnatal shift from depolarizing to hyperpolarizing
GABAergic responses, whereas the novel KCC2a isoform
obviously supports some vital functions of lower brain
structures (Uvarov et al. 2007).
However, the role of KCC2 in neuronal development
seems to cover a wider scope than that of its action
on GABAergic and glycinergic responses. A recent
collaboration between four groups at the Neuroscience
Center identified a novel morphogenetic role for KCC2
in regulating spiny excitatory synapse maturation,
implicating it in the coordinated maturation of inhibitory
and excitatory synapses (Li et al. 2007). Cultured KCC2deficient neurons were found to have aberrant, long
filopodia-like spines (Figure, panel b). Importantly, the
spine phenotype could be rescued by transfecting the
KCC2-deficient neurons with a KCC2 deletion construct
incapable of mediating K-Cl cotransport.
Another novel role for KCC2 was suggested by
Riekki et al. (2008) who studied short-term facilitation at
glutamatergic synapses using ‘physiological’ stimulation
patterns. Surprisingly, the observed difference in synaptic
dynamics between wild-type mice and mice with
reduced KCC2 protein levels was not dependent on
GABA-A receptor-mediated inhibition (Figure, panel c),
but was probably due to a change in activity-dependent
extracellular K+ transients, leading to changes in terminal
depolarization and transmitter release during repetitious
neuronal firing. The finding is a new and intriguing aspect
of the role of KCC2 in modulating of excitatory synaptic
signaling.
a
1a
1b
b
2
26
KCC2 null
WT
c
20 p / 10 Hz
Normalized EPSC amplitude
6
2.0
20 pA
250 ms
1.8
1.6
1.4
1.2
1.0
0.8
0.6
WT
KCC2 hypo/null
0.4
0.2
0
5
10
Pulse number
15
20
New roles for KCC2
a) Two KCC2 splice forms are generated by alternate
promoter and first exon usage.
b) Dendritic protrusions are longer in KCC2 null mutant
neurons.
c) Recordings of wild-type and KCC2-deficient
neurons after repetitive stimulation in the presence of
picrotoxin.
Blaesse, P., Airaksinen, M.S., Rivera, C., and Kaila,
K. (2009). Cation-chloride cotransporters and neuronal
function. Neuron (accepted).
ANNUAL REPORT 2008
Li, H., Khirurg, S., Cai, C., Ludwig, A., Kolikova, J.,
Afzalov, R., Coleman, S.K., Lauri, S., Airaksinen, M.S.,
Keinänen, K., Khiroug, L., Saarma, M., Kaila, K., and
Rivera, C. (2007). KCC2 interacts with the dendritic
cytoskeleton to promote spine development. Neuron
56: 1019-1033.
Riekki, R., Pavlov, I., Tornberg, J., Lauri, S., Airaksinen,
M.S., and Taira, T. (2008). Altered synaptic dynamics but
normal long-term plasticity in mice lacking hyperpolarizing
GABA-AR-mediated inhibition. J. Neurophysiol. 99(6):
3075-3089.
Uvarov, P., Ludwig, A., Markkanen, M., Prunsild,
P., Kaila, K., Delpire, E., Timmusk, T., Rivera, C., and
Airaksinen, M.S. (2007). A novel N-terminal isoform of
the neuron-specific K-Cl cotransporter KCC2. J. Biol.
Chem. 28(42): 30570-30576.
Enhancing neuronal plasticity in
the adult brain
Eero Castrén
Neuronal plasticity, which refers to changes in network
structure and function of large numbers of neurons, is
believed to underlie many brain functions, including
learning, memory, and emotionality. These networks are
laid down during brain development and their gradual
refinement is guided by neuronal activity reflecting
environmental stimuli or generated intrinsically (Katz et
al. 1996).
Neuronal networks are particularly plastic during the
critical periods of early postnatal development, during
which large changes in the structure of developing
networks take place (Hensch et al. 2005). Abnormal
environmental input, such as imbalanced use of the
eyes (caused by, for example, crossed eyes), may cause
the network to reflect this abnormal environment. If
the environmental condition is not corrected during the
critical period, typically before school age, the network
may permanently remain abnormal, as neuronal plasticity
dramatically decreases after this critical period. This is why
doctors patch the better eye of children with crossed eye,
to encourage the use of the weaker eye, facilitating the
cortical network to form in such a way that both eyes
are equally represented. Otherwise, the weaker eye loses
its connectivity with the visual cortex, and poor vision in
this eye will be permanent. While small-scale plasticity
remains in the adult cerebral cortex, plasticity is normally
not sufficiently strong to repair the abnormally formed
network even if the environmental imbalance is corrected
and the use of the weak eye is encouraged.
Recent results do, however, suggest that neuronal
plasticity can be boosted in the adult brain such that
networks reflecting abnormal developmental environment
can be restructured. If adult rats are placed in an enriched
housing environment and given access to toys, peers, and
a running wheel, cortical plasticity is enhanced and vision
of a weak eye can be rescued if its use is encouraged by
patching the better eye (Sale et al. 2007). Moreover,
we recently showed, in collaboration with an Italian
research group, that antidepressant drugs reactivate
critical period plasticity in adult rats (Maya Vetencourt
et al. 2008). If rats with poor vision in one eye - because
it was patched during postnatal development - have the
weak eye uncovered in adulthood and the better eye
patched in conjunction with receiving treatment with an
antidepressant drug, the vision of the weak eye could be
completely recovered. Possibly antidepressant drugs can
restore critical period plasticity also in other brain regions.
Reorganization of developmentally miswired networks to
better reflect normal environmental stimuli might be one
mechanism by which antidepressant drugs bring about
mood recovery in depressed patients.
Katz, L.C., and Shatz, C.J. (1996). Synaptic activity
and the construction of cortical circuits. Science 274:
1133-1138.
Hensch, T.K. (2005). Critical period plasticity in local
cortical circuits. Nat. Rev. Neurosci. 6: 877-888.
Sale, A., Maya Vetencourt, J.F., Medini, P., Cenni,
M.C., Baroncelli, L., De Pasquale, R., and Maffei, L.
(2007). Environmental enrichment in adulthood promotes
amblyopia recovery through a reduction of intracortical
inhibition. Nat. Neurosci. 10: 679-681.
Maya Vetencourt, J.F., Sale, A., Viegi, A., Baroncelli, L.,
De Pasquale, R., O’Leary, O.F., Castrén, E., and Maffei, L.
(2008). The Antidepressant Fluoxetine Restores Plasticity
in the Adult Visual Cortex. Science 320: 385-388.
7
ANNUAL REPORT 2008
8
Endogenous activity in the
immature brain: from basic
science to clinical studies and
applications
and to the erroneous (but frequent) extrapolation of
theories and therapies based on research in adults to
preterm and fullterm infants. A prominent example here
is anticonvulsant medication, which has little beneficial
effects in neonates.
Kai Kaila
Spontaneous (endogenous) activity in the immature
brain is generally thought to be of crucial importance
in the wiring and developmental plasticity of neuronal
connections. In this field of research, a very fruitful
convergence of various techniques and research themes
has taken place in our laboratory during the last few
years. Our major goal has been to study the molecular
and cellular bases of endogenous activity in developing
cortical structures of rats and mice, with a special focus
on GABAergic transmission and neuronal ion regulation.
We work in vitro on brain slices and in vivo on early
postnatal pups. This has enabled us to elucidate the
precise roles of some key mechanisms (e.g. depolarizing
GABA transmission and pacemaker actions of principal
neurons) in the ontogeny of sharp potentials in the
hippocampus. We are currently extending this work
on the mechanisms underlying slow neocortical activity
transients, SATs (see figure).
The above studies provide a solid foundation
for parallel research, done in collaboration with Dr.
Sampsa Vanhatalo’s team at Helsinki University Central
Hospital, where early cortical activity is studied in
human preterm babies. Here, the rodent-pup models
are useful because, from the viewpoint of neocortical
maturation, the newborn mouse or rat pup corresponds
to a human fetus at the start of the third trimester of
pregnancy. A major breakthrough in this collaboration
was the development and implementation of full-band
EEG (FbEEG) for recording slow cortical events in human
preterms. Our aims are (1) to use and develop the FbEEG
for routine monitoring in the Neonatal Intensive Care
Unit; (2) to use the information obtained to improve
current diagnostics and prognostics of preterm brain
dysfunctions; and (3) to bridge the “pediatric gap”. The
immature brain is qualitatively different from the adult
one at the cellular, molecular, and network levels. By
the term “pediatric gap”, we refer to this difference
X
10-20 Hz
0-40 Hz
5-10 Hz
0-40 Hz
Bridging the gap. The “pediatric gap”, indicated by a
red arrow and an X, implies an erroneous extrapolation
of clinical theories and applications from the adult to
the neonate brain. Bridging the gap can be done using
rodent pups as research models (black arrows). A striking
similarity in neocortical activity of preterm babies and
rat pups is seen using FbEEG techniques.
Kaila, K., Blaesse, P., and Sipilä, S.T. (2009).
Development of GABAergic signaling: from molecules
to emerging networks. In: Oxford Handbook of
Developmental Behavioral Neuroscience, Eds. Blumberg,
M.S. et al., Oxford University Press (in press).
Vanhatalo, S., and Kaila, K. (2009). Emergence of
spontaneous and evoked EEG activity in the human
brain. In: The Newborn Brain: Neuroscience and Clinical
Applications, Eds. Lagercrantz, H. et al., 2nd Ed.,
Cambridge University Press (in press).
ANNUAL REPORT 2008
Mapping neuronal assemblies
in the human brain
with the amplitude of faster (1-40 Hz) EEG oscillations,
indicating that the temporal scales of cortical assemblies
span at least four orders of magnitude.
J. Matias Palva & Satu Palva
Functionally specialized and anatomically distributed
cortical regions represent features and feature conjunctions
in sensory data. Rhythmic interactions among these brain
areas are essential for the selection and integration of
neuronal feature representations into cognitive object
representations. Brain activity, however, takes place
concurrently on many temporal and spatial scales. The
questions of how slow and fast neuronal processes
interact and how large-scale cognitive processing
coordinates local assemblies are known as the crossscale binding problem. Palva et al. (2007) proposed that
slow and large-scale attentional and executive networks
interact with and top-down modulate the faster and
more local sensory and motor networks through crossfrequency phase interactions.
Human brain activity can be studied with high
temporal and spatial accuracy by magneto- (MEG)
and electroencephalography (EEG). Mapping spatial,
temporal, and spectral interactions in such data is,
however, a computationally daunting task. Palva et
al. (submitted) have developed techniques for singletrial time-frequency analyses of phase and amplitude
dynamics. In particular, novel methods now allow the
mapping of inter-areal within- and cross-frequency phase
interactions with optimal anatomical precision. These
analyses revealed a number of transient and anatomically
distributed neuronal assemblies during the encoding and
retention periods of a visual short-term memory (vSTM)
task. As hypothesized by Palva et al. (2007), these data
show that phase-stable alpha- and beta-frequency band
oscillations in prefrontal and posterior parietal cortices are
related to the retention of multiple object representations
in vSTM.
A study by Monto et al. (2008) highlights the
multiscale nature of ongoing brain activity. Full-band EEG
recordings revealed infra-slow (0.01-0.1 Hz) fluctuations
in human subjects performing a somatosensory detection
task. Interestingly, the phase of infra-slow EEG fluctuations
was locked to the behavioral stimulus-detection dynamics.
In addition, these fluctuations were also phase-coupled
Palva, S., and Palva, J.M. (2007). New vistas for
alpha-frequency band oscillations. Trends Neurosci. 30:
150–158.
Monto, S., Palva, S., Voipio, J., and Palva, J.M. (2008).
Very slow EEG fluctuations predict the dynamics of
stimulus detection and oscillation amplitudes in humans.
J. Neurosci. 28: 8268–8272.
a) 1:1-phase synchrony binds cortical assemblies, whereas
cross-frequency (here 1:3) phase synchrony underlies
cross-scale integration (Palva et al., in preparation).
b) Phase (green line) of ongoing infra-slow fluctuations
predicts whether sensory stimuli become consciously
perceived (blue ticks) or remain unnoticed (red ticks)
(Monto et al. 2008).
9
ANNUAL REPORT 2008
10
Organization of the Neuroscience Center
Scientific Advisory Board
Board
Director
Administration
Core Facilities
•
•
•
•
Research and
Teaching Areas
• Molecular and Cellular Neuroscience
• Developmental Neuroscience
• Cognitive and Systems Neuroscience
• Basic Research of the Nervous
Systems Diseases
Mouse Transgenic Unit
Mouse Behavioural Unit
Neuronal Cell Culture Unit
Zebrafish Unit
Network
Activities
• Adjunct Professors
• Faculty Departments
• Folkhälsan
• Helsinki University of Technology
• Institute of Biotechnology
• National Institute for Health and Welfare
Commercialization
Program
ANNUAL REPORT 2008
Research Groups
-containing transmembrane proteins (LRRTMs) using
genetically modified mice (Laakso, Paatero).
Recent Progress
The mission of the Neuroscience Center is
to carry out excellent and multidisciplinary
research on the development, normal functions
and disorders of the nervous system. Research
and teaching in the NC focus on the following
four areas: molecular and cellular neuroscience,
developmental neuroscience, cognitive and
systems neuroscience, and basic research of
the nervous system diseases. The research
groups work in at least one of the research
areas of the NC. In 2008, there were eleven
research groups working in the NC.
GDNF Family Receptors,
KCC2, and Novel LRR
Proteins in Nervous
System Development and
Pathophysiology
Matti Airaksinen
Phone +358 9 191 57650
[email protected]
Description of the Project
The Airaksinen group is currently investigating 1) the
biology of the glial cell line-derived neurotrophic factor
(GDNF) family in cutaneous and gastric innervation and
inflammation (Kupari); 2) the physiological role and
regulation of neuronal K-Cl cotransporter KCC2, a key
molecule in inhibitory neurotransmission (Blaesse et al.
2009), in particular, novel isoforms and mechanisms
that drive KCC2 gene expression selectively in mature
neurons and how lack of KCC2 affects brain function
(Markkanen, Uvarov); and 3) the physiological function
of a novel family of neuronal leucine-rich repeat (LRR)
Using KCC2-deficient mouse lines created in the lab,
we have examined the specific role of hyperpolarizing
inhibition in mouse behavior and electrophysiology
(collaboration with Drs. Sari Lauri and Tomi Taira;
Tornberg et al. 2007, Riekki et al. 2008) and have shown
a novel structural role for KCC2 in spine development
(collaboration led by Dr. Claudio Rivera; Li et al. 2007).
Our recent work has identified a novel isoform of KCC2
with a unique N-terminus that includes a putative SPAK
kinase-binding site (Uvarov et al. 2007). Analysis of
expression and available mouse lines indicates that the
new KCC2a isoform supports vital neuronal functions
in the brain stem and spinal cord, whereas the other
isoform (KCC2b) is responsible for the developmental
shift of GABAergic responses.
The LRRTM family members are expressed by
overlapping subpopulations of CNS neurons. Interestingly,
a collaboration led by Dr. Clyde Franks (Oxford University)
has identified LRRTM1 as an imprinted gene and the
first putative genetic influence on human handedness
(Francks et al. 2007). This suggests that LRRTM1 is a
candidate gene for involvement in neurodevelopmental
disorders and may have played a role in human cognitive
and behavioral evolution. A putative cellular basis for this
linkage was recently provided by a new collaboration,
led by Dr. Ann-Marie Craig (University of Vancouver),
which identified LRRTM proteins as synaptic organizers
(Linhoff et al. 2009). Consistent with this idea, LRRTMs
localize to excitatory synapses and can induce presynaptic
differentiation of contacting axons in vitro, and LRRTM1deficient mice show altered distribution of excitatory
synaptic markers in vivo. Moreover, LRRTM3-deficient
mice exhibit distinct behavioral phenotypes (Laakso et
al. 2008 Soc. Neurosci. Abstract).
Personnel in 2008
Group leader: Matti Airaksinen, MD, PhD, Docent
Graduate students: Jussi Kupari, MSc; Tiina Laakso,
MSc; Marika Markkanen, MSc; Pavel Uvarov, MSc
Technician: Kaija Berg
11
ANNUAL REPORT 2008
12
Selected publications
Airaksinen, M.S., and Saarma, M. (2002). GDNF
family neurotrophic factors: receptor mechanisms,
biological functions and therapeutic utility. Nature Rev.
Neurosci. 3: 383-394.
Rossi, J., Herzig, K.H., Võikar, V., Hiltunen, P.H.,
Segerstråle, M., and Airaksinen, M.S. (2003). Alimentary
tract innervation deficits and dysfunction in mice lacking
GDNF family receptor α2. J. Clin. Invest. 112: 707-716.
Lindfors, P.H., Võikar, V., Rossi, J., and Airaksinen, M.S.
(2006). Deficient nonpeptidergic epidermis innervation
and reduced inflammatory pain in GDNF family receptor
α2 knockout mice. J. Neurosci. 26: 1953-1960.
Uvarov, P., Markkanen, M., Ludvig, A., Rivera, C., and
Airaksinen, M.S. (2006). Upregulation of the neuronspecific K+/Cl- cotransporter expression by transcription
factor early growth response 4. J. Neurosci. 26: 1346313473.
Francks, C., Maegawa, S., Laurén, J., Velayos-Baeza,
A., Colella, S., Groszer, M., McAuley, E.Z., Caffrey, T.M.,
Timmusk, T., Matsumoto-Itaba, N., Nicod, J., Xiong,
L., Joober, R., Nanba, E., Richardson, A.J., Riley, B.P.,
Strittmatter, S.M., Fisher, S.E., Wade-Martins, R., Rouleau,
G.A., Stein, J.F., Ragoussis, J., Kendler, K.S., Airaksinen,
M.S., DeLisi, L.E., Oshimura, M., and Monaco, A.P. (2007).
The maternally suppressed gene LRRTM1 is associated
paternally with handedness and schizophrenia. Mol.
Psychiatry 12: 1129-1139.
Uvarov, P., Ludwig, A., Markkanen, M., Prunsild,
P., Kaila, K., Delpire, E., Timmusk, T., Rivera, C., and
Airaksinen, M.S. (2007). A novel N-terminal isoform of
the neuron-specific K-Cl cotransporter KCC2. J. Biol.
Chem. 28: 30570-30576.
Linhoff, M.W., Laurén, J., Cassidy, R.M., Dobie, F.A.,
Nygaard, H.B., Airaksinen, M.S., Strittmatter, S.M., and
Craig, A.M. (2009). An unbiased expression screen for
synaptogenic proteins identifies the LRRTM protein family
as synaptic organizers. Neuron 61(5): 734-49.
Blaesse, P., Airaksinen, M.S., Rivera, C., and Kaila,
K. (2009). Cation-chloride cotransporters and neuronal
function. Neuron 61(6): 820-838.
ANNUAL REPORT 2008
Sigrid Jusélius Laboratory
Physiological,
Pathophysiological, and
Pharmacological Roles
of Neurotrophins in the
Adult Brain
Eero Castrén
Phone +358-9-191 57626
[email protected]
neurotrophic factor) in learning, memory, emotionality,
and CNS drug action.
We have also investigated the roles of neurotrophins
and the epigenetic regulation of the BDNF gene in the
long-term behavioral effects of perinatal drug or toxin
exposure. We are using cultured neurons, organotypic
cultures, and DNA microarrays, to uncover the effects and
mechanisms of neurotrophins and neuropsychiatric drugs
in the brain. Future aims are to exploit our models to
understand the roles and consequences of neurotrophinmediated plastic responses in drug action, and to develop
new models to search for drugs that will influence the
effects of endogenous neurotrophins in the brain.
Personnel in 2008
We are interested in the physiological and pathophysiological
roles of neuronal plasticity and neurotrophins in the
adult brain. Of particular interest is the role of plasticity
and neurotrophins in the mechanisms of action of
antidepressants and other CNS drugs. We have developed
mouse models of increased and decreased signaling of
the trkB neurotrophin receptor in neurons. Using these
mice and other experimental systems, we have shown
a critical role of neurotrophin BDNF (brain-derived
Group leader: Sigrid Jusélius Professor in Neuroscience,
Research Director Eero Castrén, MD, PhD
Post-doctoral fellows: Heidi Anthoni, PhD; Antonio Di
Lieto, MD, PhD; Nina Karpova, PhD; Tomi Rantamäki,
PhD (pharm.); Ettore Tiraboschi, PhD; Xuefei Wu, PhD
Graduate students: Henri Autio, MSc (pharm); MarieEstelle Hokkanen, MSc; Juha Knuuttila, MSc; Jesse
Lindholm, MSc (pharm)
Undergraduate student: Liisa Vesa
Technician: Outi Nikkilä
13
ANNUAL REPORT 2008
14
Selected publications
Sairanen, M., Lucas, G., Ernfors, P., Castrén, M., and
Castrén, E. (2005). BDNF and antidepressant drugs have
different but coordinated effects on neuronal turnover,
proliferation and survival in the adult dentate gyrus. J.
Neurosci. 25: 1089-1094.
Castrén, E. (2005). Is mood chemistry? Nature Rev.
Neurosci. 6: 241-246.
Castrén, M., Tervonen, T., Kärkkäinen, V., Heinonen,
S., Castrén, E., Larsson, K., Bakker, C.E., Oostra, B.A., and
Åkerman, K.E.O. (2005). Altered Differentiation of Neural
Stem Cells in Fragile X Syndrome. Proc. Natl. Acad. Sci.
USA 102: 17834-17839.
Castrén, E., and Tanila, H. (2006). Neurotrophins and
dementia – keeping in touch. Neuron 51: 1-3.
Rantamäki, T., Hendolin, P., Kankaanpää, A.,
Mijatovic, J., Piepponen, P., Domenici, E., Chao, M.V.,
Männistö, P.T., and Castrén, E. (2007). Pharmacologically
diverse antidepressants rapidly activate Brain-derived
neurotrophic factor (BDNF) receptor trkB and induce
phospholipase-Cγ signaling pathways in mouse brain.
Neuropsychopharmacology 32: 2152–2162.
Maya Vetencourt, J.F., Sale, A., Viegi, A., Baroncelli,
L., De Pasquale, R., O’Leary, O.F., Castrén, E., and Maffei,
L. (2008). The antidepressant fluoxetine restores plasticity
in the adult visual cortex. Science 320: 385-388.
Onishchenko, N., Karpova, N., Sabri, F., Castrén, E.,
and Ceccatelli, S. (2008). Long-lasting depression-like
behavior and epigenetic changes of BDNF gene expression
induced by perinatal exposure to methylmercury. J.
Neurochem. 106: 1378-1387.
Karpova, N., Lindholm, J., Pruunsild, P., Timmusk,
T., and Castrén, E. (2008). Long-lasting behavioural
and molecular alterations induced by early postnatal
fluoxetine exposure are restored by chronic fluoxetine
treatment in adult mice. Eur. Neuropsychopharmacology
19: 97-108.
O’Leary, O.F., Wu, X., and Castrén, E. (2008). Chronic
fluoxetine treatment increases expression of synaptic
proteins in the hippocampus of ovariectomized rats and
mice. Psychoneuroendocrinology, Epub ahead of print.
Tervonen, T.A., Louhivuori, V., Sun, X., Hokkanen, M.E., Kratochwil, C.F., Zebryk, P., Castrén, E., and Castrén,
M.L. (2008). Aberrant differentiation of glutamatergic
cells in neocortex of mouse model for fragile X syndrome.
Neurobiol. Disease, Epub ahead of print.
Endocytic Pathway in
Late-Onset Alzheimer’s
Disease: New Models and
Therapeutic Approaches
Henri J. Huttunen
Phone +358 9 191 57646
[email protected]
Currently, only symptomatic treatment options are
available for Alzheimer’s disease (AD), the most
common form of dementia in the elderly. Although
several promising mechanism-based approaches are in
active drug development, they have faced unexpected
difficulties with specificity, clinical safety, and efficacy
(e.g. γ-secretase inhibitors and Aß immunization). Better
understanding of the cellular mechanisms by which Aß(ßamyloid peptide) generation becomes dysregulated in
neurons, and how Aß exerts its deleterious effects on
cognitive functions at the level of the synapse is essential
for elucidating the etiology of AD and developing
new mechanism-based therapeutic strategies for this
devastating disease.
Most current AD research focuses on how to reverse
or delay the cerebral amyloid pathology typically seen
in patients with AD as well as in animal models of AD.
Amyloid plaques are composed of aggregated ß-amyloid
peptide (Aß), the pathologically central molecule thought
to initiate a cascade that culminates in neurotoxicity
and neurodegeneration, causing memory loss and
cognitive decline. Importantly, an increasing number
of studies in animal models of AD have suggested that
soluble, oligomeric Aß species strongly affect synaptic
functions. Specifically, these diffusible Aß species promote
internalization of both AMPA and NMDA receptors in
the postsynaptic nerve terminals, leading to depression
of excitatory synaptic transmission (AMPA) and reduced
induction of long-term potentiation (LTP; NMDA). These
findings may explain the apparent two-stage nature
of AD. Moderate accumulation of (mostly) soluble Aß
interferes with basic glutamatergic synaptic transmission,
ANNUAL REPORT 2008
resulting in gradual memory loss (mild AD cases) before
significant plaque pathology has developed. Later on,
highly elevated levels of Aß lead to deposition of amyloid
to senile plaques with concomitant neuronal cell death
and more severe disturbation of cognitive functions
(moderate to severe AD cases).
The basic proteolytic events resulting in the generation
of the pathologically central Aß peptide from its precursor
protein APP are now well characterized. How Aß
production becomes dysregulated early in the course of
the disease remains poorly understood. Recent findings
suggest that the very first pathological changes preceding
the appearance of senile plaques are enlarged neuronal
endosomes. Importantly, most neuronal Aß generation
is thought to occur in endosomes, but what kind of
metabolic stimuli (or lack of them) lead to endosomal
pathology and enhanced Aß generation remains
unknown. Better understanding of how endosomal
Aß generation becomes dysregulated in neurons and
how the elevated levels of soluble Aß lead to changes
in synaptic functions requires appropriate models to
study these events in neurons. In summary, this work
is expected to provide new models and therapeutic
approaches targeting the early pathophysiological events
in late-onset AD.
The aims of this research project are as follows:
(1) to establish novel cell and animal models of
targeted endosomal dysfunction that enhance generation
of endogenous Aß,
(2) to characterize the effects of endosomal
dysfunction on dendritic spine
morphology and dynamics as well
as postsynaptic glutamate receptor
(AMPA/NMDA) trafficking, and
(3) to identify novel, smallmolecule compounds that modulate
endosome-Golgi trafficking of APP
and BACE1, the two key proteins
for Aß generation.
Personnel in 2008
Project leader: Henri Huttunen, PhD, docent
Undergraduate students: Kai Kysenius; Niko-Petteri
Nykänen; Prasanna Sakha
Selected publications
Huttunen, H.J., Puglielli, L., Ellis, B.C., MacKenzie
Ingano, L.A., and Kovacs, D.M. (2009). A Novel ACATSensitive Proteolytic Pathway of the Amyloid Precursor
Protein Inhibits Aß Generation in AC29 Cells. J. Mol.
Neurosci. 37(1): 6-15.
Huttunen, H.J., and Kovacs, D.M. (2008). ACAT as
a Drug Target for Alzheimer’s Disease. Neurodeg. Dis.
5(3-4): 212-214.
Huttunen, H.J., Guenette, S.Y., Peach, C., Greco,
C., Barren, C., Tanzi, R.E., and Kovacs, D.M. (2007).
HtrA2 Regulates APP Metabolism through ER-associated
Degradation. J. Biol. Chem. 282(38): 28285-28295.
Huttunen, H.J., Greco, C., and Kovacs, D.M.
(2007). Knockdown of ACAT-1 Reduces Amyloidogenic
Processing of APP. FEBS Letters 581: 1688-1692.
Hutter-Paier, B., Huttunen, H.J., Puglielli, L., Eckman,
C.B., Kim, D.Y., Hofmeister, A., Moir, R.D., Domnitz, S.B.,
Frosch, M.P., Windisch, M., and Kovacs, D.M. (2004). The
ACAT Inhibitor CP-113,818 Markedly Reduces Amyloid
Pathology in a Mouse Model of Alzheimer’s Disease.
Neuron 44: 227-238.
15
ANNUAL REPORT 2008
16
Mechanisms of Electrical,
Ionic, and Trophic
Signaling in the Brain
Kai Kaila
Phone +358 9 191 59860
[email protected]
In projects related to our laboratory’s collaboration
with the Neuroscience Center, we have focused on the
following topics:
1. Early Network Activity: GDPs and Sharp Waves
GABA is generally thought to have an excitatory
role in immature brain tissue. Using a wide spectrum of
electrophysiological techniques (whole-cell, cell-attached,
perforated-patch, and field potential recordings) in
hippocampal slices, we found that the temporal patterns
of early activity (“Giant Depolarizing Potentials; GDPs”)
are set by the intrinsic properties of glutamatergic
pyramidal neurons, while GABAergic transmission has a
temporally nonpatterned role (Sipilä et al. 2005, 2006).
This has led to a profound revision of the ideas generally
accepted in this field of research, especially as GDP-type
activity is thought to play a key role in the development
of neuronal connections during brain maturation. The
close homology between the in vitro GDPs and in vivo
sharp waves (SPWs) has been studied in experiments
ANNUAL REPORT 2008
that now also include chronic intrahippocampal and
intracortical recordings from nonanesthetized rat pups
(Schuchmann et al. 2006; for review, see Sipilä and
Kaila 2007, 2009). At the moment, we are working on
adult mouse slices and adult mice in vivo to further test
the hypothesis that GDPs and SPWs are homologous
network events. A striking result obtained recently is
that under some experimental conditions as well as in
some transgenic mice, GDPs are generated in neonatal
slices in the absence of depolarizing GABA actions (work
in progress). These findings have numerous implications
for neonatal network activity in general, and they also
highlight the homology between GDPs and SPWs.
2. Expression Patterns and Functions of KCC2 and
CAVII
In previous work, we have put a lot of emphasis on the
role of transcriptional/translational mechanisms in “ionic
plasticity” mediated by KCC2. Data obtained during the
last year have convincingly shown that KCC2 functionality
is strongly modulated by membrane trafficking. In this
context, we are re-examining the rate of KCC2 protein
turnover. This project involves also the chloride uptake
transporter, NKCC1.
The expression of the carbonic anhydrase isoform
CAVII at the end of the second postnatal week leads
to a major qualitative change in the properties of
GABAergic transmission (for review, see Rivera et al.
2005). There is reason to believe that CAVII is also a
target of anticonvulsant drugs (Ruusuvuori et al. 2004;
Vullo et al. 2005). A CAVII knockout mouse has been
constructed by our collaborator, Dr. Christian Hübner,
and recent experiments using these mice have provided
support for the idea that CAVII is a key molecule in certain
epileptiform syndromes (see also 4 below).
3. Quantitative Assay of Neuronal Chloride
Homeostasis: Subcellular Compartments
In collaboration with Dr. Leonard Khiroug, we have
devised a rigorous assay of the efficacy of chloride
transport at the single-neuron level (Khirug et al. 2005).
This technique is based on somatic chloride loading and
laser uncaging of GABA along the dendrite, which gives
a direct estimate of the intraneuronal chloride gradient
maintained by KCC2. We have applied this technique
in combination with gramicidin patch clamping to
investigate subcellular “microdomains” in neurons where
chloride shows a nonhomogeneous distribution. In a
recent publication (Khirug et al. 2008), we demonstrate
the presence of a pronounced steady-state gradient of
intracellular chloride, which leads to hyperpolarizing
GABA response in dendrites and depolarizing (NKCC1dependent) responses at the axon initial segment of
principal neurons. This is an extremely important finding
that will provide new mechanistic data on how axoaxonal interneurons (chandelier cells) act on their targets.
This and many other functions of neuronal chloride
transporters will be discussed in an invited extensive
review (Neuron, in press).
4. Pathophysiology of Slow Endogenous Activity in
the Immature Rat Hippocampus and Neocortex: Febrile
Seizures
Using constant in vivo recordings of the cortex of
rat and mouse pups, we have investigated systems-level
properties of GDPs as well as maturation of hippocampalneocortical functional connectivity. This work has led
to identification of a novel mechanism underlying
hyperthermic convulsions in a widely accepted model
of febrile seizures (Schuchmann et al. 2006). In addition
to these basic studies, pilot work is being conducted at
Helsinki University Central Hospital to examine whether
the mechanism identified in rat pups can be used to
design novel therapeutic strategies in the treatment
of fever-related epilepsies. We have recently obtained
evidence that 5% carbon dioxide suppresses epileptic
activity also in adult rats, and strikingly, also in adult
humans.
5. Spontaneous Activity in the Immature Human
Cortex
We have extended our work on early cortical
spontaneous activity to the preterm human brain. Using
DC-EEG recordings from preterm babies, we have shown
in collaboration with Dr. Vanhatalo (Helsinki University
Central Hospital) that slow cortical activity transients of
the kind described in early postnatal rodents are also
generated by the immature human cortex (Vanhatalo
et al. 2005; for review, see Vanhatalo and Kaila 2009).
These results are significant from the viewpoints of both
basic and clinical science. In view of the high sensitivity
of spontaneous activity to brain trauma, one of our aims
is to promote such recordings for routine use in NICUs
(Neonatal Intensive Care Units) worldwide.
17
ANNUAL REPORT 2008
18
6. Role of the subplate in generation of early cortical
network events
We have started collaboration with Dr. Patrick
Kanold (University of Maryland) to examine the role of
the subplate in the generation of spontaneous events in
the immature neocortex. We use an immunotoxin-based
procedure for selective ablation of subplate neurons in
neonate rats and mice. The data obtained provide strong
evidence for a key role of the subplate in the generation
of early network activity. These results are important
also from a clinical point of view because the subplate
is perhaps the most vulnerable structure to exogenous
disturbances (such as anoxia/ischemia) in the developing
brain.
Personnel in 2008
Group leader: Professor, Research Director Kai Kaila,
PhD
Post-doctoral fellows: Ramil Afzalov, PhD; Peter Blaesse,
PhD; Sampsa Sipilä, MD, PhD; Else Tolner, PhD
Graduate students: Faraz Ahmad, MSc; Mohamed
Helmy, MB, BCh; Kristiina Huttu, MSc; Stanislav Khirug,
MSc; Ilya Kirilkin, MD; Alessandro Marabelli, MSc; Eva
Ruusuvuori, MSc; Alexey Yukin, MSc
Undergraduate student: Martin Puskarjov
Coordinator: Katri Wegelius, PhD
Technician: Kirsi Ahde
Selected publications
Blaesse, P., Airaksinen, M.S., Rivera, C., and Kaila,
K (2008). Cation-chloride cotransporters and neuronal
function. Neuron, invited review, in press.
Vanhatalo, S., and Kaila, K. (2008). Emergence of
spontaneous and evoked EEG activity in the human
brain. In: The Newborn Brain: Neuroscience and Clinical
Applications, Eds. Lagercrantz, H., Hanson, M., Evrard,
P., and Rod, C. 2nd edition. Cambridge University Press,
Cambridge, in press.
Khirug, S., Yamada, J., Afzalov, R., Voipio, J., Khiroug,
L., and Kaila, K. 2008. GABAergic depolarization of the
axon initial segment in cortical principal neurons is caused
by the Na-K-2Cl cotransporter NKCC1. J. Neurosci.
28(18): 4635-4639.
Colonnese, M.T., Phillips, M.A., Constantine-Paton,
M., Kaila, K., and Jasanoff, A. (2008). Development of
hemodynamic responses and functional connectivity in
rat somatosensory cortex. Nat. Neurosci.11: 72-79.
Li, H., Khirug, S., Cai, C., Ludwig, A., Blaesse,
P., Kolikova, J., Afzalov, R., Coleman, S.K., Lauri, S.,
Airaksinen, M.S., Keinänen, K., Khiroug, L., Saarma, M.,
Kaila, K., and Rivera, C. (2007). KCC2 Interacts with the
Dendritic Cytoskeleton to Promote Spine Development.
Neuron 56: 1019-1033.
Schuchmann, S., Schmitz, S., Rivera, C., Vanhatalo,
S., Mackie, K., Sipila, S.T., Voipio, J., and Kaila, K.
(2006). Experimental febrile seizures are precipitated
by a hyperthermia-induced respiratory alkalosis. Nature
Med. 12: 817-823.
Sipilä, S., Huttu, K., Soltesz, I., Voipio, J., and Kaila,
K. (2005). Depolarizing GABA acts on intrinsically
bursting pyramidal neurons to drive ‘Giant Depolarizing
Potentials’ in the immature hippocampus. J. Neurosci.
25: 5280-5289.
Rivera, C., Voipio, J., Thomas-Crusells, J., Li, H., Emri,
Z., Sipilä, S., Payne, J.A., Minichiello, L., Saarma, M.,
and Kaila, K. (2004). Mechanism of activity-dependent
downregulation of the neuron-specific K-Cl cotransporter
KCC2. J. Neurosci. 24: 4683-4691.
Vanhatalo, S., Palva, J.M., Holmes, M.D., Miller, J.W.,
Voipio, J., and Kaila, K. (2004). Infraslow oscillations
modulate excitability and interictal epileptic activity in
the human cortex during sleep. Proc. Natl. Acad. Sci.
USA 101: 5053-5057.
Buzsáki, G., Kaila, K., and Raichle, M. (2007).
Inhibition and brain work. Neuron 56(5): 771-783.
ANNUAL REPORT 2008
Functional and
Morphological Plasticity
of Tripartite Synapse
Leonard Khirug
Phone +358-9-191 57644
[email protected]
During development and in the course of everyday
life, synaptic transmission undergoes plastic changes
manifested as morphological and functional modulation
of both excitatory and inhibitory synapses. While synaptic
plasticity has been in the spotlight of neuroscience
for some years now, its mechanisms remain poorly
understood. A major challenge lies in uncovering the
complex interactions between the multiple chemical and
electrical signaling pathways in the synapse.
The research of our group focuses on studying
synapses and their structural and functional plasticity
by utilizing a combination of advanced optical and
electrophysiological techniques. We examine the synapse
as a tripartite structure composed of a presynaptic neuron
(terminal), a postsynaptic neuron (dendritic spine), and a
perisynaptic astrocyte that enwraps the first two synaptic
components and actively participates in the overall
functional and morphological plasticity. Experiments are
carried out in brain slices as well as on cultured neurons
and involve confocal microscopy combined with patch
19
ANNUAL REPORT 2008
20
clamp, local photolysis of caged compounds, calcium
imaging, and total internal reflection fluorescence (TIRF)
microscopy.
The major lines of our current research include 1) the
role of mitochondrial signaling and Ca2+ homeostasis in
neurodegeneration; 2) the regulation of mitochondrial
motility in relation to synaptic function; 3) mechanisms
of ATP release from astrocytes and purinergic regulation
of synaptic transmission; 4) activity-dependent trafficking
of receptors and channels to the plasma membrane;
and 5) mechanisms by which GABAergic synapses shift
between inhibitory and excitatory modes of action.
Some of our most recent findings (published and
unpublished) include 1) characterization of time course
and Ca2+ dependence of ATP exocytosis in astrocytes; 2)
demonstration of impaired mitochondrial Ca2+ buffering
in CLN8-related neurodegeneration (in collaboration
with the Lehesjoki group); and 3) structural role of the
neuronal K-Cl cotransporter in stabilizing glutamatergic
synapses (in collaboration with the groups of Rivera,
Kaila, and others).
Personnel in 2008
Group leader: Leonard Khirug, PhD, docent, Academy
Research Fellow
Post-doctoral fellows: Ramil Afzalov, PhD; Julia
Kolikova, PhD; Elena Kremneva, PhD; Evgeny
Pryazhnikov, MD, PhD; Sergey Savelyev, PhD
Graduate students: Ilya Kirilkin, MD; Dmitry
Molotkov; Vikram Sharma
Undergraduate students: Artjom Dugan; Elizaveta
Tilli
Selected publications
Khiroug, L., Sokolova, E., Giniatullin, R., Afzalov,
R., and Nistri, A. (1998). Recovery from desensitization
of neuronal nicotinic acetylcholine receptors of rat
chromaffin cells is modulated by intracellular calcium
through distinct second messengers. J. Neurosci. 18:
2458-2466.
Miyata, M., Finch, E.A., Khiroug, L., Hashimoto, K.,
Emdad, L., Siddiq, A., Hayasaka, S., Dekker-Ohno, K.,
Inouye, M., Takagishi, Y., Augustine, G.J., and Kano, M.
(2000). Local IP3-mediated signaling required in purkinje
cell dendritic spines for long-term synaptic depression.
Neuron 28(1): 233-244.
Khiroug, L., Giniatullin, R., Klein, R.C., Fayuk, D.,
and Yakel, J.L. (2003). Functional mapping and Ca2+
regulation of nicotinic acetylcholine receptor channels
in rat hippocampal CA1 neurons. J. Neurosci. 23: 90249031.
Khirug, S., Huttu, K., Ludwig, A., Smirnov, S., Voipio,
J., Rivera, C., Kaila, K., and Khiroug, L. (2005). Distinct
properties of functional KCC2 expression in immature
mouse hippocampal neurons in culture and in acute slices.
Eur. J. Neurosci. 21(4): 899-904.
Safiulina, V.F., Afzalov, R., Khiroug, L., Cherubini,
E., and Giniatullin, R. (2006). Reactive oxygen species
mediate the potentiating effect of ATP on GABAergic
synaptic transmission in the immature hippocampus. J.
Biol. Chem. 281: 23464-23470.
Kolikova, J., Afzalov, R., Giniatullina, A., Surin, A.,
Giniatullin, R., and Khiroug, L. (2006). Calcium-dependent
trapping of mitochondria near plasma membrane in
stimulated astrocytes. Brain Cell Biol. 35: 75-86.
Tanaka, K., Khiroug, L., Santamaria, F., Doi, T.,
Ogasawara, H., Ellis-Davies, G., Kawato, M., and
Augustine, G.J. (2007). Ca2+ requirements for cerebellar
long-term synaptic depression: role for a postsynaptic
leaky integrator. Neuron 54(5): 787-800.
Li, H., Khirug, S., Cai, C., Ludwig, A., Kolikova,
J., Afzalov, R., Coleman, S., Lauri, S., Airaksinen, M.,
Keinänen, K., Khiroug, L., Saarma, M., Kaila, K., and
Rivera, C. (2007). Neuron 56(6): 1019-1033.
Pryazhnikov, E., and Khiroug, L. (2008). Submicromolar increase in [Ca2+]i triggers delayed exocytosis
of ATP in cultured astrocytes. Glia 56(1): 38-49.
Khirug, S., Yamada, J., Afzalov, R., Voipio, J., Khiroug,
L., and Kaila, K. (2008). GABAergic depolarization of the
axon initial segment in cortical principal neurons is caused
by the Na-K-2Cl cotransporter NKCC1. J. Neurosci.
28(18): 4635-4639.
ANNUAL REPORT 2008
Signaling Mechanisms
Guiding Functional
Maturation of
Glutamatergic Synapses
Sari Lauri
Phone +358 191 59865
[email protected]
Formation of neuronal circuits is a highly dynamic
process of rapid and concurrent formation and
elimination of synaptic connections. During this early
development, immature neuronal networks typically
display spontaneous, rhythmic activity, which is thought
to be instrumental for the development of synaptic
circuitry.
Exactly how activity shapes synaptic connectivity
during development and the molecular mechanisms
underlying these processes remain largely unknown. The
key questions are what are the cellular and molecular
mechanisms that link electrical activity to changes in
synaptic structure and how are these regulated during
development. To understand this process, we focus on
studying the glutamate receptor mechanisms to detect
specific patterns of endogenous activity in the immature
hippocampus as well as in the downstream signaling
cascades converting receptor activity into long-lasting
synaptic imprints.
Our experimental approach involves the use of in
vitro electrophysiological techniques in combination
with pharmacological and local genetic manipulation
of neuronal activity in various neonatal hippocampal
preparations.
Our current main research interests are as follows:
1) uncovering the physiological functions and
developmental regulation of kainate–type ionotropic
glutamate receptors in the immature hippocampus;
and
2) exploring the activity-dependent mechanisms
guiding presynaptic maturation at developing
glutamatergic synapses. We aim to understand how
the fast Hebbian and the slow, homeostatic plasticity
mechanisms operate in the developing circuitry and
how they might control the transition from immature to
mature presynaptic function.
21
ANNUAL REPORT 2008
22
Personnel in 2008
Project leader: Sari Lauri, PhD, docent, Academy
Research Fellow
Group leader: Tomi Taira, PhD, docent
Post-doctoral fellow: Sabine Koch, PhD
Graduate students: Johanna Huupponen, MSc; Juuso
Juuri, MSc; Marko Sallert, MSc.; Aino Vesikansa, MSc
Undergraduate student: Suvi Pousi
Mechanisms of Neurologic
Disease: from Gene
Mutation to Pathogenesis
Anna-Elina Lehesjoki
Phone +358 9 191 25072
[email protected]
Selected publications
Huupponen, J., Molchanova, S., Taira, T., and Lauri,
S.E. (2007). Susceptibility for homeostatic plasticity
is downregulated in parallel with maturation of the
hippocampal synaptic circuitry. J. Physiol. 581(Pt 2):
505-514.
Vesikansa, A., Sallert, M., Taira, T., and Lauri, S.E.
(2007). Activation of kainate receptors controls density
of functional glutamatergic synapses in the area CA1 of
hippocampus. J. Physiol. 583(Pt 1): 145-157.
Sallert, M., Malkki, H., Segerstråle, M., Taira, T., and
Lauri, S.E. (2007). Effects of the kainate receptor agonist
ATPA on glutamatergic synaptic transmission and plasticity
during early postnatal development. Neuropharmacology
52(6): 1354-1365.
Lauri, S.E., Vesikansa, A., Segerstråle, M., Collingridge,
G.L., Isaac, J.T.R., and Taira, T. (2006). Functional
maturation of CA1 synapses involves activity-dependent
loss of tonic kainate receptor-mediated inhibition of
glutamate release. Neuron 50(3): 415-429.
Lauri, S.E., Segerstråle, M., Vesikansa, A., Maingret,
F., Mulle, C., Collingridge, G.L., Isaac, J.T.R., and Taira,
T. (2005). Endogenous activation of kainate receptors
regulates glutamate release and network activity in
the developing hippocampus. J. Neuroscience 25(18):
4473.
Lauri, S.E., Bortolotto, Z.A., Bleakman, D., Ornstein,
P.L., Lodge, D., Isaac, J.T.R., and Collingridge, G.L.
(2003). A role for Ca2+ stores in kainate-dependent
synaptic facilitation and LTP at mossy fibre synapses in
the hippocampus. Neuron 39: 327-341.
Lauri, S.E., Bortolotto, Z.A, Bleakman, D., Ornstein,
P.L., Lodge, D., Isaac, J.T.R., and Collingridge, G.L. (2001).
A critical role of a facilitatory kainate autoreceptor in
mossy fibre LTP. Neuron 32: 697-709.
Description of the project and recent
progress
The research of our group aims at understanding the
molecular basis of specific human inherited disorders
through mapping and cloning of underlying defective
genes, followed by functional analyses of gene products
utilizing cellular and animal models. This will form the
basis for the development of rational methods for
prevention and treatment of these disorders.
Our past achievements include identification of the
genes underlying Progressive myoclonus epilepsy (EPM1),
Northern epilepsy (CLN8), Mulibrey nanism (MUL), Cohen
syndrome, and Marinesco-Sjögren syndrome. Of these,
we have proceeded to functional analyses in EPM1,
CLN8, and MUL. The EPM1 gene encodes cystatin B
(CSTB), a previously described and characterized cysteine
protease inhibitor. The CLN8 gene encodes a novel
endoplasmic reticulum resident transmembrane protein
that belongs to the TRAM-Lag1p-CLN8 (TLC) family of
proteins with lipid-sensing domains. The TRIM37 gene
underlying MUL encodes a novel peroxisomal protein.
The localization, molecular function, and interactions
of all three proteins are investigated in tissue-specific
cellular models. The existing mouse models for EPM1
and CLN8 are characterized using neuroanatomical,
immunohistochemical, and magnetic resonance
imaging methods. We have generated a novel Trim37deficient mouse model for MUL and have initiated its
characterization. Gene expression and metabolic profiling
in mice are underway to identify underlying metabolic
pathways.
As another important line of research, the group
aims to identify genes underlying more common forms
of idiopathic epilepsy, including susceptibility genes for
ANNUAL REPORT 2008
epilepsy phenotypes with complex inheritance. New
epilepsy genes will be identified through linkage analysis
of rare, dominantly inherited variants of these epilepsies,
followed by positional candidate gene analysis through
sequencing of functional candidates and associationbased analyses.
Our recent work has concentrated on further
elucidation of the two recently identified genes, SIL1 for
Marinesco-Sjögren syndrome and MFSD8 for a variant
form of late-infantile onset neuronal ceroid lipofuscinosis.
Several new mutations have been identified and
characterized, allowing further delineation of the
associated phenotypes.
The search for novel neuronal ceroid lipofuscinosis
genes has continued using a SNP-chip-based homozygosity
mapping approach, resulting in several candidate genomic
regions to await further dissection. Using the same
approach, the long search for the gene underlying the
autosomal recessive inherited PEHO syndrome (Progressive
Encephalopathy with Edema, Hypsarrhythmia, and
Opticus atrophy) was finally successful, with one genomic
region identified in Finnish families. We are continuing
the sequence analysis of functional candidate genes for
idiopathic generalized epilepsy within the EU-funded
EPICURE project (www.epicureproject.eu/).
The focus in the EPM1 project has been on the
neuronal death mechanisms associated with CSTB
deficiency, especially on characterizing the role for CSTB as
a regulator of neuronal survival during oxidative stress. Our
data so far define a novel pathophysiological mechanism
related to EPM1, whereby CSTB deficiency couples
oxidative stress to neuronal death and degeneration,
implying that intact CSTB-Cathepsin B signaling is critical
for maintaining cellular homeostasis under oxidative
stress conditions. To characterize the anatomical and
cellular basis of EPM1-associated neuronal death
and hyperexcitability in Cstb-/- mice, we initiated, in
collaboration with Dr. Jonathan Cooper at King’s College
London, a systematic analysis of the neuronal and glial
components of the central nervous system of Cstb-/- mice
at different stages of disease progression using unbiased
stereological methodology. Further, in collaboration with
Dr. Olli Gröhn, we will be performing in vivo magnetic
resonance imaging (MRI) and proton magnetic resonance
23
ANNUAL REPORT 2008
24
spectroscopy (1H MRS), followed by ex vivo DTI-MRI,
utilizing the experimental MRI scanners of the National
Bio-NMR Facility at the A.I.Virtanen Institute, University
of Kuopio.
In the CLN8 project, we focus on functional studies
based on our findings in mRNA and lipidomic profiling
of neuronal tissue in the mnd mouse model. These
include studies on myelination, axonal conductance, and
oligodendrocyte function and maturation in vitro, as well
as on neuronal and glial development utilizing neuronal
progenitor cells. Unbiased stereological methodology and
in vivo MRI as well as ex vivo DTI-MRI are utilized in the
characterization of CLN8-associated disease pathology
in mnd mice (in collaboration with Drs. Cooper and
Gröhn). Calcium homeostasis of mnd neurons is being
investigated in collaboration with Dr. Leo Khirug at the
Neuroscience Center.
Personnel in 2008
Group leader: Professor, Research Director Anna-Elina
Lehesjoki, MD, PhD
Post-doctoral fellows: Anna-Kaisa Anttonen, MD, PhD;
Nina Aula-Kahanpää, PhD; Tarja Joensuu, PhD; Outi
Kopra, PhD; Anne Polvi, PhD; Kaisa Valli-Jaakola, PhD
Graduate students: Maria Kousi, MSc; Mervi Kuronen,
MSc; Anni Laari, MSc; Otto Manninen, MSc; Auli Sirén,
MD; Saara Tegelberg, MSc
Undergraduate students: Katariina Mattila, med. stud;
Minnamari Talvitie, BSc
Technicians and other technical staff: Mira Aronen;
Paula Hakala; Hanna Hellgrén; Hanna Pauloff; Teija-Tuulia
Toivonen
Selected publications
Pennacchio, L.A., Lehesjoki, A.-E., Stone, N.E.,
Willour, V.L., Virtaneva, K., Miao, J., D’Amato, E.,
Ramirez, L., Faham, M., Koskiniemi, M., Warrington,
J., Norio, R., de la Chapelle, A., Cox, D.R., and Myers,
R.M. (1996). Mutations in the gene encoding cystatin B
cause progressive myoclonus epilepsy (EPM1). Science
271: 1731-1734.
Virtaneva, K., D’Amato, E., Miao, J., Koskiniemi, M.,
Norio, R., Avanzini, G., Franceschetti, S., Michelucci, R.,
Tassinari, C.A., Omer, S., Pennacchio, L.A., Myers, R.M.,
Dieguez-Lucena, J.L., Krahe, R., de la Chapelle, A., and
Lehesjoki, A.-E. (1997). Unstable minisatellite expansion
causing recessively inherited myoclonus epilepsy, EPM1.
Nature Genet. 15: 393-396.
Ranta, S., Zhang, Y., Ross, B., Lonka, L., Takkunen,
E., Messer, A., Sharp, J., Wheeler, R., More, S., Liu, W.,
Soares, M.B., de Fatima Bonaldo, M., Hirvasniemi, A., de
la Chapelle, A., Gilliam, T.C., and Lehesjoki, A.-E. (1999).
The neuronal ceroid lipofuscinosis in human EPMR and
mnd mutant mice are associated with mutations in CLN8.
Nature Genet. 23: 233-236.
Avela, K., Lipsanen-Nyman, M., Idänheimo, N.,
Seemanová, E., Rosengren, S., Mäkelä, T.P., Perheentupa,
J., de la Chapelle, A., and Lehesjoki, A.-E. (2000). Gene
encoding a new RING-B-box-coiled-coil protein is mutated
in mulibrey nanism. Nature Genet. 25: 298-301.
Lonka, L., Kyttälä, A., Ranta, S., Jalanko, A., and
Lehesjoki, A.-E. (2000). The neuronal ceroid lipofuscinosis
CLN8 membrane protein is a resident of the endoplasmic
reticulum. Hum. Mol. Genet. 9: 1691-1697.
Kallijärvi, J., Avela, K., Lipsanen-Nyman, M., Ulmanen,
I., and Lehesjoki, A.-E. (2002). The TRIM37 gene
encodes a peroxisomal RING-B-box-coiled-coil protein:
Classification of Mulibrey nanism as a new peroxisomal
disorder. Am. J. Hum. Genet. 70: 1215-1228.
Kolehmainen, J., Black, G.C.M., Saarinen, A.,
Chandler, K., Träskelin, A.-L., Perveen, R., Kivitie-Kallio,
S., Norio, R., Warburg, M., Fryns, J.-P., de la Chapelle,
A., and Lehesjoki, A.-E. (2003). Cohen syndrome is
caused by mutations in a novel gene, COH1, encoding a
transmembrane protein with a presumed role in vesiclemediated sorting and intracellular protein transport. Am.
J. Hum. Genet. 72: 1359-1369.
Anttonen, A.K., Mahjneh, I., Hämäläinen, R.H., LagierTourenne, C., Kopra, O., Waris, L., Anttonen, M., Joensuu,
T., Kalimo, H., Paetau, A., Tranebjaerg, L., Chaigne, D.,
Koenig, M., Eeg-Olofsson, O., Udd, B., Somer, M., Somer,
H., and Lehesjoki, A.E. (2005). The gene disrupted in
Marinesco-Sjögren syndrome encodes SIL1, an HSPA5
cochaperone. Nature Genet. 37: 1309-1311.
Siintola, E., Topcu, M., Aula, N., Lohi, H., Minassian,
B.A., Paterson, A.D., Liu, X.Q., Wilson, C., Lahtinen, U.,
Anttonen, A.K., and Lehesjoki, A.E. (2007). The novel
neuronal ceroid lipofuscinosis gene MFSD8 encodes a
putative lysosomal transporter. Am. J. Hum. Genet. 81:
136-146.
ANNUAL REPORT 2008
Systems-Level Mechanisms
of Perception, Cognition,
and Action in the Human
Brain
J. Matias Palva
Phone +358 9 191 57653
[email protected]
Neuronal processing is spatially, temporally, and spectrally
scattered. A central question in neuroscience is how
this scattered neuronal activity is bound to coherent
perception, cognition, and action. Our mission is to
characterize the neuronal-network level mechanisms
underlying this binding. We hypothesize that two specific
forms of neuronal interactions, n:m-phase synchrony
and nested oscillations, mediate the coordination and
integration of neuronal processing distributed into
hierarchies of network oscillations in many frequency
bands.
We use magneto- and electroencephalography (MEG
and EEG), cortically constrained minimum-norm estimate
(MNE) inverse modeling, and functional magnetic
resonance imaging (fMRI) to noninvasively investigate
neuronal dynamics in the human brain. These noninvasive
data are complemented by intracranial recordings in
human patients awaiting epilepsy surgery. Data analysis,
management, and visualization methods and tools are
continuously developed for handling these multimodal
data.
Personnel in 2008
Project leader: J. Matias Palva, PhD, docent
Post-doctoral fellow: Satu Palva, PhD
Graduate students: Shrikanth Kulashekhar, BSc; Simo
Monto, MSc Tech; Santeri Rouhinen, MSc
Selected publications
Monto, S., Palva, S., Voipio, J., and Palva, J.M. (2008).
Very slow EEG fluctuations predict the dynamics of
stimulus detection and oscillation amplitudes in humans.
J. Neurosci. 28: 8268-8272.
Palva, S., and Palva, J.M. (2007). New vistas for
alpha-frequency band oscillations. Trends Neurosci. 30:
150–158.
Monto, S., Vanhatalo, S., Holmes, M.D., and Palva,
J.M. (2007). Epileptogenic neocortical networks are
revealed by abnormal temporal dynamics in seizure-free
subdural EEG. Cereb. Cortex 17(6): 1386-1393.
25
26
ANNUAL REPORT 2008
Palva, S., Linkenkaer-Hansen, K., Näätänen, R., and
Palva, J.M. (2005). Early neural correlates of conscious
somatosensory detection. J. Neurosci. 25: 5248–5258.
Palva, J.M., Palva, S., and Kaila, K. (2005). Phase
synchrony among neuronal oscillations in the human
cortex. J. Neurosci. 25: 3962–3972.
Linkenkaer-Hansen, K., Nikulin, V.V., Palva, S.,
Ilmoniemi, R.J., and Palva, J.M. (2004). Prestimulus
oscillations enhance psychophysical performance in
humans. J. Neurosci. 24: 10186–10190.
Vanhatalo, S., Palva, J.M., Holmes, M.D., Miller, J.W.,
Voipio, J., and Kaila, K. (2004). Infraslow oscillations
modulate excitability and interictal epileptic activity in
the human cortex during sleep. Proc. Natl. Acad. Sci.
USA 101: 5053–5057.
Palva, S., Palva, J.M., Shtyrov, Y. , Kujala, T., Ilmoniemi,
R., Kaila, K., and Näätänen, R. (2002). Distinct gammaband evoked responses to speech and non-speech sounds
in humans. J. Neurosci. 22: RC211.
Linkenkaer-Hansen, K., Nikouline, V.V., Palva,
J.M., and Ilmoniemi, R.J. (2001). Long-range temporal
correlations and scaling behavior in human brain
oscillations. J. Neurosci. 21: 1370–1377.
Palva, J.M., Lämsä, K., Lauri, S., Rauvala, H., Kaila, K.,
and Taira, T. (2000). Fast network oscillations in newborn
rat hippocampus in vitro. J. Neurosci. 20: 1170–1178.
Modulatory
Neurotransmitter Systems
and Their Role in Brain
Diseases
Pertti Panula
Phone +358-9-191 25263
[email protected]
The modulatory neurotransmitter systems include several
aminergic and peptidergic neuron systems and their long
projections in the vertebrate brain. These transmitters use
numerous G protein-coupled receptors, which share signal
transduction systems in cells. In addition to regulating
key physiological functions, many of these systems are
involved in important human neurodegenerative diseases.
Our research focuses on identification and functional
roles of new modulatory systems, and their functional
roles in brain diseases.
A particular target is the histaminergic system, which
has important interactions with other aminergic (e.g.
dopaminergic) and peptidergic (e.g. orexin) systems
in regulation of, for instance, sleep, diurnal rhythms,
feeding, and addiction. Using new algorithms, novel
receptors were identified in databases. They were cloned
in several species and expression analyses suggest that
they regulate important functions. New methods were
developed to use zebrafish in combined studies of
complex neuronal systems. Confocal and two-photon
imaging systems allow three-dimensional imaging of
whole neurotransmitter systems in the zebrafish brain at
a time when the fish already display complex behaviors.
Quantitative behavioral analysis systems were developed
to simultaneously analyze the behaviour of up to 100 fish.
Identification and cloning of fish orthologs of important
human disease genes with poorly known functions
and translation inhibition and identification of mutant
zebrafish are followed by phenotypic analysis using the
new imaging and behavioural methods. The methods
created in the project also allow use of zebrafish in the
development of new drugs for central nervous system
disorders, including those related to motor functions,
ANNUAL REPORT 2008
anxiety-related behaviour, and memory. In addition to the
dopamine system, the serotonin system suffers specific
damage in zebrafish following exposure to MPTP, a
Parkinson’s disease-related neurotoxin.
Personnel in 2008
Group leader: Professor, Research Director Pertti
Panula, MD, PhD
Post-doctoral fellows: Yu-Chia Chen, PhD; Kaj
Karlstedt, PhD; Hisaaki Kudo, PhD; Yaroslav Lyubimov,
PhD; Saara Nuutinen, PhD
Graduate students: Raphaela Kaisler, MSc; Ilmari
Määttänen, MSc; Madhusmita Priyadarshini, MSc;
Stanislav Rozov, MSc; Ville Sallinen, MD; Maria
Sundvik, MSc
Undergraduate students: Tiia Ojala; Gabija Toleikyte
Fish Manager: Henri Koivula, BSc
Technicians: Anna Lehtonen, BSc; Susanna Norrbacka
Selected publications
Haas, H.L., and Panula, P. (2003). The role of histamine
and the tuberomamillary nucleus in the brain. Nat. Rev.
Neurosci. 4: 121-130.
Engström, M., Brandt, A., Wurster, S., Savola, J.M., and Panula, P. (2003). Prolactin-releasing peptide
has high affinity and efficacy on the neuropeptide FF2
receptor. J. Pharmacol. Exp. Ther. 305: 825-832.
Kalliomäki, M., Pertovaara, A., Brandt, A., Wei, H.,
Pietilä, P., Kalmari, J., Xu, M., Kalso, E., and Panula, P.
(2004). Prolactin-releasing peptide affects pain, allodynia
and autonomic reflexes through medullary mechanisms.
Neuropharmacology 46: 412-424.
Kaslin, J., Nystedt, J.M., Östergård, M., Peitsaro, N.,
and Panula, P. (2004). The orexin/hypocretin system in
zebrafish is connected to the aminergic and cholinergic
systems. J. Neurosci. 24: 2678-2689.
Anichtchik, O.V., Kaslin, J., Peitsaro, N., Scheinin, M.,
and Panula, P. (2004). Neurochemical and behavioral
changes in zebrafish Danio rerio after systemic
administration of 6-hydroxydopamine and 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine. J. Neurochem. 88:
443-453.
Kukko-Lukjanov, T.-K., Soini, S., Michelsen, K.A.,
Panula, P., and Holopainen, I.E. (2006). Histaminergic
neurons protect the developing hippocampus from
kainic acid-induced neuronal damage in an organotypic
co-culture system. J. Neurosci. 26: 1088-1097.
Peitsaro, N., Sundvik, M., Anichtchik, O.V., Kaslin,
J., and Panula, P. (2007). Identification of zebrafish
histamine H1, H2 and H3 receptors and effects of
histaminergic ligands on behavior. Biochem. Pharmacol.
73: 1205-1214.
Bongers, G., Sallmen, T., Passani, M.B., Mariottini, C.,
Wendelin, D., Lozada, A., Marle, A., Navis, M., Blandina,
P., Bakker, R.A., Panula, P., and Leurs, R. (2007). The
Akt/GSK-3beta axis as a new signaling pathway of the
histamine H(3) receptor. J. Neurochem. 103: 248-258.
Sallinen, V., Torkko, V., Sundvik, M., Reenilä, I.,
Khrustalyov, D., Kaslin, J., and Panula, P. (2009). MPTP
and MPP+ target specific aminergic cell populations in
larval zebrafish. J. Neurochem. 108(3): 719-731.
27
ANNUAL REPORT 2008
28
Cell Surface and
Extracellular Matrix
Molecules in Neuronal
Development, Plasticity,
and Disorders
Heikki Rauvala
Phone +358-9-191 57621
[email protected]
Formation of neuronal connections during development
is a prerequisite for the establishment of functional neural
networks in the adult organism. To grow to their targets,
the growth cones of neurites (axons and dendrites) sense
extracellular cues for migration. Cell surface adhesion
molecules, extracellular matrix proteins, and soluble
growth factors act as cues for growth cone migration,
enabling formation of neuronal connections. In general,
brain plasticity recapitulates developmental mechanisms
that are also important for functions of the adult nervous
system, such as memory and learning.
Based on neurite outgrowth assays, we have
previously defined two ligands of heparan sulfate
proteoglycans, HB-GAM (heparin-binding growthassociated molecule; pleiotrophin) and amphoterin
(HMGB1). The transmembrane heparan sulfate
proteoglycan N-syndecan (syndecan-3) acts as a receptor
of HB-GAM. Structure-function analysis suggests that the
two thrombospondin type I (TSR) repeats of HB-GAM
bind to N-syndecan. Very recent studies have shown
that HB-GAM/N-syndecan-dependent cell signaling
regulates radial migration of neurons and is required for
the development of the laminar structure of the cerebral
cortex. Furthermore, these studies suggest a cross-talk
between N-syndecan and EGFR (epidermal growth factor
receptor). Besides their developmental role, HB-GAM and
ANNUAL REPORT 2008
its receptor N-syndecan are implicated in the regulation
of synaptic plasticity and behaviour in the adult.
In addition to heparin/heparan sulfates, amphoterin
binds to the immunoglobulin superfamily protein RAGE
(receptor for advanced glycation end-products), which
mediates the neurite outgrowth-promoting signal of
amphoterin. Amphoterin/RAGE is involved in migration
control of many cell types during development, tumor
spread, and inflammation. Studies on amphoterin/
RAGE have resulted in a novel research line, where
communication of neurons with immune cells is
explored.
AMIGO (amphoterin-induced gene and orf) has been
identified as an amphoterin-induced gene in hippocampal
neurons using ordered differential display. AMIGO defines
a novel gene family with three closely related members
(AMIGO, AMIGO 2, and AMIGO 3) and is suggested to
mediate fasciculation of neurites.
Roles of HB-GAM, amphoterin/RAGE, and the
AMIGOs in vivo are examined using mutant mouse
approaches. Analysis of transgenic mice includes
histology, immunohistochemistry, electrophysiology, and
behavioural phenotyping. The signalling mechanisms of
the proteins are elucidated using methods of molecular
cell biology and structural biology.
Personnel in 2008
Group leader: Professor, Director Heikki Rauvala, MD,
PhD
Post-doctoral fellows: Tommi Kajander, PhD; Natalia
Kulesskaya, PhD; Mikhail Paveliev, PhD; Ari Rouhiainen,
PhD; Li Tian, PhD
Graduate students: Kathleen Gransalke, MSc;
Marjaana Kiiltomäki, MSc; Juha Kuja-Panula, MSc;
Evgeny Kulesskiy, MSc; Lauri Mankki, MSc; Päivi
Vanttola, MSc; Xiang Zhao, MSc
Undergraduate student: Lotta Sundelin
Technicians: Seija Lågas; Eeva-Liisa Saarikalle
Selected publications
HB-GAM/N-syndecan (syndecan-3)
Lauri, S.E., Kaukinen, S., Kinnunen, T., Ylinen, A., Imai,
S., Kaila, K., Taira, T., and Rauvala, H. (1999). Regulatory
role and molecular interactions of a cell-surface heparan
sulfate proteoglycan (N-syndecan) in hippocampal longterm potentiation. J. Neurosci. 19: 1226-1235.
Reizes, O., Lincecum, J., Wang, Z., Goldberger, O.,
Huang, L., Kaksonen, M., Ahima, R., Hinkes, M.T., Barsh,
G.S., Rauvala, H., and Bernfield, M. (2001). Transgenic
expression of syndecan-1 uncovers a physiological control
of feeding behavior by syndecan-3. Cell 106: 105-116.
Raulo, E., Tumova, S., Pavlov, I., Pekkanen, M., Hienola,
A., Klankki, E., Kalkkinen, N., Taira, T., Kilpeläinen, I., and
Rauvala, H. (2005). The two thrombospondin type I repeat
domains of HB-GAM bind to heparin/heparan sulfate and
regulate neurite extension and plasticity in hippocampal
neurons. J. Biol. Chem. 280: 41576-41583.
Hienola, A., Tumova, S., Kulesskiy, E., and Rauvala, H.
(2006). N-Syndecan deficiency impairs neural migration
in brain. J. Cell Biol. 174(4): 569-580.
Amphoterin/Ig superfamily proteins/AMIGO
Kuja-Panula, J., Kiiltomäki, M., Yamashiro, T.,
Rouhiainen, A., and Rauvala, H. (2003). AMIGO,
a transmembrane protein implicated in axon tract
development, defines a novel protein family with leucinerich repeats. J. Cell Biol. 160: 963-973.
Rouhiainen, A., Kuja-Panula, J., Wilkman, E.,
Pakkanen, J., Stenfors, J., Tuominen, R.K., Lepäntalo,
M., Carpen, O., Parkkinen, J., and Rauvala, H. (2004).
Regulation of monocyte migration by amphoterin
(HMGB1). Blood 104: 1174-1182.
Rouhiainen, A., Tumova, S., Valmu, L., Kalkkinen,
N., and Rauvala, H. (2007). Pivotal Advance: Analysis of
proinflammatory activity of highly purified eukaryotic
recombinant HMGB1 (amphoterin). J. Leukoc. Biol. 81:
49-58.
Rauvala, H., and Rouhiainen, A. (2007). RAGE as a
receptor of HMGB1 (Amphoterin): Roles in health and
disease. Curr. Mol. Med. 7: 725-734.
Tian, L., Lappalainen, J., Autero, M., Hänninen,
S., Rauvala, H., and Gahmberg, C.G. (2008). Shedded
neuronal ICAM-5 suppresses T cell activation. Blood
111(7): 3615-3625.
Tian, L., Rauvala, H., and Gahmberg, C.G. (2009).
Neuronal regulation of immune responses in the central
nervous system. Trends Immunol., Epub ahead of print
Jan 12.
29
ANNUAL REPORT 2008
30
Activity-Dependent
Development and
Plasticity in the
Hippocampus
Tomi Taira
Phone +358 9 191 59855
[email protected]
Description of the Project and Recent
Progress
During development our brain evolves from a sparsely
connected set of nerve cells into a finely tuned neuronal
network capable of delicate information processing.
Spontaneous electrical activity, i.e. electrical events
emerging within the neuronal network itself rather than
being evoked by external inputs, provides important cues
for the precise neural connections to be formed, but we
have only just begun to understand the elaborateness of
this process. Our project aims at elucidating the activitydependent mechanisms that regulate development and
plasticity of neuronal connections in the mammalian
brain, and how these mechanisms contribute to the
functional maturation of neuronal networks.
We employ a multi-methodological approach using a
combination of electrophysiological, molecular biological,
and imaging techniques. Moreover, a wide range of
experimental models (in vitro, in vivo) are used in parallel,
ANNUAL REPORT 2008
thus providing an immediate, physiologically relevant
framework for our studies.
We have recently identified a new kainate-type
glutamate receptor (KAR) that regulates presynaptic
maturation in developing hippocampal neurons (Lauri et
al. 2006). It provides a novel mechanism for activation of
‘silent’ synapses during early development, and is thus
likely to play a critical role in the formation of functional
synaptic connections in the hippocampus. At the level
of the neuronal network, KARs via modulating synaptic
inputs to both interneurons and pyramidal cells regulate
synchronous activity in the developing hippocampus
(Palva et al. 2000; Lamsa et al. 2000; Lauri et al. 2005).
Interestingly, this kind of activity is probably linked to
certain early behavioral states (Lahtinen et al. 2002).
The level of neuronal network activity can in turn have
a critical impact on the maturation of the hippocampal
circuitry. Our work has demonstrated that the density
of glutamatergic synapses is rapidly regulated by the
overall levels of neuronal activity in the intact immature
hippocampus (Lauri et al. 2003). This regulation is strongly
dependent on the developmental stage of the tissue, and
it appears to have different ‘critical periods’ for excitatory
(glutamatergic) and inhibitory (GABAergic) synapses
(Huupponen et al. 2007).
Personnel in 2008
Group leader: Tomi Taira, PhD, docent
Project leader: Sari Lauri, PhD, docent
Post-doctoral fellows: Vernon Clarke, PhD; Svetlana
Molchanova, PhD
Graduate students: Johanna Huupponen, MSc; Juuso
Juuri, MSc; Marko Sallert, MSc; Mikael Segerstråle,
MSc; Aino Vesikansa, MSc
Undergraduate student: Annika Östman
Selected publications
Lauri, S.E., Palmer, M., Vesikansa, A., Segerstråle,
M., Taira, T., and Collingridge, G. (2007). Presynaptic
mechanisms of expression of LTP at CA1 synapses in the
hippocampus. Neuroharmacology 52(1): 1-11.
Huupponen, J., Molchanova, S., Taira, T., and Lauri,
S.E. (2007). Susceptibility for homeostatic plasticity
is downregulated in parallel with maturation of the
hippocampal synaptic circuitry. J. Physiology 581(Pt2):
505–514.
Lauri, S.E., Vesikansa, A., Segerståle, M., Collingridge,
G., Isaac, J., and Taira, T. (2006). Functional maturation
of CA1 synapses involves activity-dependent loss of
tonic kainate receptor-mediated inhibition of glutamate
release. Neuron 50: 415-429.
Lauri, S.E., Segertstrale, M., Vesikansa, A., Maingret,
F., Mulle, C., Collingridge, G., Isaac, J., and Taira, T. (2005).
Endogenous activation of kainate receptors inhibits
glutamatergic transmission and modulates network
activity in the developing hippocampus. J. Neurosci.
25(18): 4473-4484.
Pavlov, I., Riekki, R., and Taira, T. (2004). Synergistic
action of GABA-A and NMDA receptors in the induction
of LTD in glutamatergic synapses in the newborn rat
hippocampus. Eur. J. Neurosci. 20: 3019-3026.
Lamsa, K., and Taira, T. (2003). Use-dependent shift
from inhibitory to excitatory GABA-A receptor action in
SP-O interneurons in the rat hippocampal CA3 area. J.
Neurophysiol. 90: 1983-1995.
Lauri, S.E., Lamsa, K., Pavlov, I., Riekki, R., Johnston,
B., Molnar, E., Rauvala, H., and Taira T. (2003). Activityblockade induces formation of functional synapses in
the newborn rat hippocampus. Mol. Cell. Neurosci. 22:
107-117.
Pavlov, I., Voikar, V., Kaksonen, M., Lauri, S., Hienola,
A., Taira, T., and Rauvala, H. (2002). Role of HeparinBinding Growth-Associated Molecule (HB-GAM) in
hippocampal LTP and spatial learning revealed by
studies on overexpressing and knockout mice. Mol. Cell.
Neurosci. 20: 330-342.
Lahtinen, H., Palva, M., Sumanen, S., Voipio, J.,
Kaila, K., and Taira, T. (2002). Postnatal development of
rat hippocampal gamma (20-80 Hz) rhythm in vivo. J.
Neurophysiol. 88: 1469-1474.
Palva, M., Lamsa, K., Lauri, S.E., Rauvala, H., Kaila,
K., and Taira, T. (2000). Fast network oscillations in the
newborn rat hippocampus in vitro. J. Neurosci. 20(3):
1170-1178.
31
32
ANNUAL REPORT 2008
Adjunct Professors
www.helsinki.fi/neurosci/adjunct_professors.html
The Neuroscience Center may also have joint
research programs and activities with other
parts of the University of Helsinki, with other
universities, research centers or related units.
The Neuroscience Center has collaboration
with four Adjunct professors to expand
and deepen the research and teaching
areas. The Adjunct professors were selected
for a three-year period starting in 2008.
Structural Biology of Targets Relevant to
Neuroscience
Adrian Goldman
Institute of Biotechnology, University of Helsinki
[email protected]
Neurobiological Basis of Dyslexia:
Susceptibility Genes and Regulatory
Networks
Juha Kere
Karolinska Institutet, Sweden; University of Helsinki,
Biomedicum Helsinki; and Folkhälsan Institute of
Genetics, Helsinki
[email protected], [email protected]
Regulation of Actin-Driven Morphological
Processes in Neurons and Radial Glia
Pekka Lappalainen
Institute of Biotechnology, University of Helsinki,
[email protected]
Neurobiological Mechanisms of Memory
Impairment in Alzheimer´s Disease
Heikki Tanila
Department of Neurobiology, A. I. Virtanen Institute,
University of Kuopio
[email protected]
ANNUAL REPORT 2008
Teaching at the
Neuroscience
Center
Eero Castrén
Phone +358 9 191 57626
[email protected]
Tomi Taira
Phone +358 9 191 59855
[email protected]
teaching provided by the NC equals the
credits required for minor subject studies in
neuroscience (25 cr), a doctoral degree (60 cr),
or to complete a major in the international
Master´s Degree Programme in Neuroscience
(120 cr). Thus, our teaching packages give
excellent opportunities to study neuroscience
for both undergraduate and postgraduate
degrees.
Master´s Degree
Programme in
Neuroscience – MNEURO
www.helsinki.fi/neuro
Strong investment in research-based teaching
is one of the central strategies of the University
of Helsinki. The position of the NC as an
interdisciplinary research institute gives it a
unique opportunity to promote this task.
Neuroscience courses have already been
organized for several years at both the Viikki
and Meilahti campuses. The NC currently
organizes several neuroscience courses
consisting of both lecture courses and handson laboratory modules both at undergraduate
and graduate level. In addition, every research
group organizes a weekly internal seminar
series, which gives the students an opportunity
to present their data and discuss their projects
with supervisors and group members. In 2008,
four doctoral and four master’s theses were
completed at the NC. Currently, 44 doctoral
theses and 16 master’s theses are under
preparation.
All courses organized by the NC are in
English. The NC provides a wide range of
neuroscience teaching that integrates recent
research with undergraduate and graduate
courses. Lectures, seminars, and laboratory
courses are designed in collaboration with
experts in teaching techniques to ensure high
efficacy and quality of teaching. Currently,
Tomi Taira, Programme leader
Phone +358 9 191 59855
[email protected]
Ulla Lahtinen, Research coordinator
Phone + 358 9 191 57625
[email protected]
In 2008, the new Master’s Degree Programme in
Neuroscience – MNEURO – was launched by the
Neuroscience Center and the Faculty of Biosciences. The
Neuroscience Center had a central role in organizing
the teaching curriculum as well as in carrying out the
teaching. The Master´s degree in neuroscience, 120 ECTS
credits, consists of obligatory (60-64 cr) and elective (5660 cr) studies. The course curriculum includes specialized
lectures and laboratory courses that cover aspects such
as molecular and cellular neuroscience, electrophysiology,
neuroanatomy, neurohistology, signalling, plasticity,
brain disorders, and developmental and computational
neuroscience. The aim of the programme is to provide
students with the knowledge and skills needed for
modern advanced and applied neuroscience research.
After completing a Master´s in neuroscience, successful
students will have the possibility of entering doctoral
programs at the University of Helsinki.
33
34
ANNUAL REPORT 2008
Five foreign students were admitted to the MNEURO
programme in autumn 2008. As students have
backgrounds in various subjects, such as molecular
biology, medicine, and psychology, special emphasis is
placed on student counselling to create individual study
plans for every student. In addition to the Neuroscience
Center and the Faculty of Biosciences, students are able
to select courses at the faculties of Medicine, Veterinary
Medicine, Science, Behavioural Sciences, and Pharmacy,
as well as at the Helsinki University of Technology.
Prasanna Sakha from Nepal is one of the students
who started the MNEURO programme in 2008. “The
programme is well structured and helps us to build a
strong basis in neuroscience” he says. He appreciates the
research- and problem-based learning approach and is
impressed by the open communication with teachers and
supervisors. He is now a trainee in Dr. Henri Huttunen´s
research group and is involved in a project investigating
molecular mechanisms of Alzheimer´s disease. Prasanna
Sakha received the University of Helsinki International
Student Grant in 2008.
MNEURO is part of the Network of European Schools
in Neuroscience, NENS. In autumn 2008, a bilateral
agreement for Erasmus exchange covering the academic
years 2008-2013 for both students and teachers with
the University of Trieste, Italy, was signed. An initial
network of five European Master´s programmes within
the Universities of Trieste, Helsinki, Bordeaux, Amsterdam,
and Coimbra was also agreed and established.
Prasanna Sakha from Nepal is one of the students who
started the MNEURO programme in 2008.
Finnish Graduate School
of Neuroscience - FGSN
www.helsinki.fi/fgsn
Kai Kaila, Chairman
Phone +358 9 191 59860
[email protected]
Katri Wegelius, Coordinator
Phone + 358 9 191 59859
[email protected]
Members of the Neuroscience Center are also closely
connected to local and national graduate schools funded
by the Ministry of Education and the Academy of Finland.
Eight of the Neuroscience Center group leaders belong to
the Management Board of the Finnish Graduate School
of Neuroscience (FGSN).
The FGSN provides 4-year positions and training for
doctoral students in different fields of neuroscience. The
31 FGSN research groups at the Universities of Helsinki,
Kuopio, Oulu and Turku, as well as at the Helsinki
University of Technology and Åbo Akademi are working
in collaboration to develop post-graduate education at a
national level in neuroscience. Research and PhD training
are based on multidisciplinary collaborations among all
disciplines relevant in neurosciences, including cellular
and molecular neuroscience, membrane transport,
electrophysiology of cells and networks, developmental
neurobiology, neurobiology at the systems level,
neuronal modeling, imaging of human brain functions,
neuropsychology, neuropathology and degenerative
diseases as well as clinical studies.
In 2008, 20 doctoral students were funded by the
FGSN (Ministry of Education) and about 30 students
by their supervisors from other sources. In addition to
postgraduate courses, the FGSN students are entitled
to guidance and administration help on their doctoral
studies as well as travel grants awarded by the FGSN.
Eight FGSN students defended her/his dissertation in
2008.
FGSN is part of the CORTEX Training Network
(Cooperation in Research and Training for European
ANNUAL REPORT 2008
Excellence in Neurosciences), a Marie Curie Mobility
Action of the EU. FGSN is also a member of the Network
of European Schools in Neuroscience, NENS, and has
ongoing collaboration with several European PhD
Programs.
Teaching Highlight
Zebrafish Neurobiology Course
August 11-15, 2008
Coordinator: Pertti Panula
Zebrafish has so far been used mainly as a model
organism in developmental biology. As a vertebrate, it
would, however, also be a good model for studying the
structural basis of behavior, as brain neurons can easily
be visualized in the larval brain at a time when the larva
already behaves as an independent fish.
A course in basic zebrafish methods and neurobiological
approaches was held in the newly opened facility in
Meilahti. The course participants – doctoral students and
postdocs from Finland, Denmark, and Russia – enjoyed
morning and afternoon practical sessions with intervening
lectures. The teachers Professors Marnie Halpern, Rob
Cornell, and Donald O’Malley covered genetic, molecular,
physiological, anatomical, and behavioral approaches.
The participants also learned basic maintenance and
breeding of the fish.
Due to the large number of applicants, not everyone
could be offered the opportunity to learn the practical
skills. However, personnel of the facility will help those
interested or in urgent need to get the training as a special
service. The next course is planned for 2010.
35
36
ANNUAL REPORT 2008
Courses Organized in 2008
www.helsinki.fi/neurosci/education.htm
920001 Introduction to Molecular and
Cellular Neuroscience
(6 ECTS credits, lectures and exam)
Responsible person: Heikki Rauvala
Participants: 30
920003 Functional Neuroanatomy and
Histology
(3 ECTS credits, lectures and exam)
Responsible person: Matti Airaksinen
Participants: 30
920007 Basic Mechanisms of Nervous
System Disorders
(6 ECTS credits, lectures and exam)
Responsible persons: Anna-Elina Lehesjoki and Pentti
Tienari
Participants: 27
522277 Electrophysiological Applications
in Neurophysiology
(5 ECTS credits, laboratory course, lectures and exam)
Responsible persons: Sari Lauri and Tomi Taira
Participants: 6
ANNUAL REPORT 2008
Neuroscience Seminar Series 2008
Coordinator: Leonard Khirug
Phone +358 9 191 57644
[email protected]
The Neuroscience Seminar Series has been organized regularly since 2003 and has proven to be an important instrument
of scientific exchange as well as student education. In 2008, 24 seminars were held by international and Finnish research
scientists, ranging from young independent researchers to prominent senior scientists. Speakers are usually invited by
the Neuroscience Center group leaders, and seminars cover a broad range of topics from neuroscience to cell biology.
The audience of 30 to 50 people consists of graduate students, postdoctoral fellows, and senior faculty members. Guest
speaker presentations are always followed by questions from the audience and lively discussions. For PhD students,
regular attendance and active participation in the Neuroscience Seminars are counted as points towards their study plan.
In addition to the main presentation, each invited speaker is encouraged to spend time with a number of group leaders
individually, engaging in more in-depth discussion of recent findings and mutually interesting scientific questions.
1.2.
Robin Willemsen (Department of Clinical Genetics, Erasmus Medical Center, University of
Rotterdam, the Netherlans): FMR1 expression: from mental retardation to FXTAS
7.2.
Graeme Black (St. Mary’s Hospital and Centre for Molecular Medicine, University of Manchester,
UK): Human cataract and ocular development
7.3.
Jiro Kasahara (Tohoku University, Japan): Behavioral and biochemical analysis of CaMKIV knock-out mice
14.3.
Elisabeth Bock and Vladimir Berezin (Department of Neuroscience and Pharmacology, Panum
Institute, University of Copenhagen, Denmark): Structure and function of NCAM; Development of
peptides derived from homophilic and heterophilic binding sites mimicking diverse NCAM functions
28.3.
Patrik Kanold (College of Life Sciences, University of Maryland, USA): Circuits that control cortical
development and plasticity
14.4.
Juan Nacher (Department of Cell Biology, University of Valencia, Spain): Slippery neurons. A role for
PSA-NCAM in the structural plasticity of the adult cerebral cortex
18.4.
Patrik Ernfors (Department of Medical Biochemistry and Biophysics, Karolinska Institute, Sweden):
Regulation of stem cell self-renewal by chromatin modification
25.4.
Marylka Uusisaari (Laboratory for Neuronal Circuit Dynamics, RIKEN Brain Science Institute, Japan):
Cerebellum and its nuclei - the black box at the back of the brain
9.5.
Pekka Lappalainen (Institute of Biotechnology, University of Helsinki, Finland):
MIM/ABBA family proteins regulate actin and plasma membrane dynamics in neurons and glial cells
37
ANNUAL REPORT 2008
38
22.5.
Kerstin Krieglstein (University of Göttingen, Germany): Molecular mechanisms of TGF-beta induced
apoptosis
23.5.
Michael Sendtner (University of Wuerzburg, Germany): Mechanisms of axonal damage and
preservation in models of motor neuron disease
30.5.
Iris Salecker (Division of Molecular Neurobiology, MRC National Institute for Medical Research,
London, UK): Regulation of axon targeting in the visual system of Drosophila
13.8.
Alexey Verkhratsky (University of Manchester, Manchester, UK): P2X receptor-mediated purinergic
transmission in the CNS
18.8.
Greg Stuart (John Curtin School of Medical Research, Australian National University, Australia):
The action potential
12.9.
Anthony-Samuel LaMantia (Department of Cell & Molecular Physiology, The University of North
Carolina at Chapel Hill, USA): When half is not enough: Consequences of 22q11 deletion syndrome for
neural development and function
23.9.
Asa Abeliovich (Taub Institute for the Aging Brain, Departments of Pathology and Cell Biology and
Neurology, Columbia University, USA): Cellular and molecular pathways in Parkinson’s disease
3.10.
Wieland B. Huttner (Max Planck Institute of Molecular Cell Biology and Genetics, Dresden,
Germany): The cell biology of neural stem and progenitor cells
20.10. Olga Vergun (Department of Neurology, University of Pittsburgh, USA): Contribution of mitochondria
to the regulation of neuronal ionic homeostasis
28.10. Per Svenningsson (Laboratory of Molecular and Cellular Neuroscience, Karolinska Institutet,
Sweden): On the role of p11 and GluR1 subunits in depression-like states
31.10. Peter Uhlhaas (Max Planck Institute for Brain Research, Frankfurt, Germany): Neural synchrony as
mechanism for pathology and development in cortical networks
21.11. Laurent Groc (CNRS, Université Bordeaux, France): Shedding new lights on the glutamate synapse
maturation using Single Particle Tracking
24.11. Claes Wahlestedt (Department of Neuroscience, Scripps Institute, Florida, USA): Regulatory RNA
27.11. Mitchell Chesler (New York University Medical Center, Departments of Neurosurgery and
Physiology and Neuroscience, USA): Regulation and role of activity dependent extracellular alkaline shifts
in the hippocampus
8.12.
Josef Rauschecker (Georgetown University, USA): Parallel processing in the auditory cortex of primates
ANNUAL REPORT 2008
Core Facilities
High-quality infrastructures are a prerequisite
for top-level research. Sophisticated technologies
used in moder n neuroscience require
centralization as core facilities used by several
research groups within and outside of the NC.
The Mouse Transgenic Unit, run in cooperation
with the Institute of Biotechnology, is
extensively used by the researchers of the NC
to study in vivo roles of molecules of interest.
Transgenic methods allow dissection of normal
and abnormal behavioral mechanisms; the
rationale to start the Mouse Behavioral Unit
was in the context of mouse transgenesis.
The Zebrafish Core Facility provides another
important model organism for neuroscience
research, in particular for developmental
and behavioral neuroscience and for disease
models. The zebrafish project operates on
both the Meilahti and the Viikki campuses,
serving as an example of active inter-campus
operations. The Neuronal Cell Culture Unit, a
key facility of the NC, is used by groups from
both campuses.
Mouse Behavioural Unit
Heikki Rauvala
Phone +358 9 191 57621
[email protected]
Mouse genetic models play a key role in the investigation of
molecular pathways underlying normal biological functions
or pathological states. The models require extensive
analysis at various levels of complexity. Behavioural testing
is an important approach in comprehensive studies aimed
at understanding psychiatric and neurological diseases.
The analysis of mouse behaviour in laboratory conditions
is undergoing rapid evolution, and a growing need exists
for expertise in this field.
The Mouse Behavioural Unit was started in 1998
to provide research groups in neurobiology with the
possibility of characterizing their mutant mice. Since
then, the Unit has substantially expanded its repertoire
of available tests and models. The systematic work for
improvement and refinement of the methods has been
recognized locally and internationally. We have therefore
been receiving an increasing number of collaboration
requests. The test battery for behavioural phenotyping
involves assessment of motor behaviour (coordination,
spontaneous activity), muscles strength (grip strength),
nociception (hot/cold plate, tail withdrawal, plantar
test, automated von Frey, paw-pressure analgesia),
sensorimotor gating (prepulse inhibition of acoustic startle
reflex), emotional behaviour (elevated plus maze, lightdark exploration, open field, Y-maze, forced swim test),
social behavior (dominance tube test, resident+intruder
test), and learning and memory (spatial navigation
in water maze, fear conditioning, conditioned taste
aversion, novel object recognition, social transmission of
food preference). Recently, the comprehensive laboratory
animal monitoring system was set up for long-term (2472 hours), automated, and noninvasive collection of
several physiological and behavioural parameters (activity,
food and water consumption, metabolic performance)
simultaneously. This year, the Unit’s abilities were
broaden by installing IntelliCage. IntelliCage is a newly
developed system that allows home-cage monitoring of
spontaneous and cognition mice behavior in a normal
social environment with minimal human influence. It will
give further insight into the welfare of the animals.
In addition to the phenotyping of mutant mice, basic
research with commonly used inbred strains is carried out
to establish baseline values and to validate models. These
studies provide important background information for
interpretation of data. More specifically, we are interested
in the interactions of genetic background, sex, and
environment in modulation of behavioural patterns. The
Unit is awaiting new animal facilities to accommodate the
space requirements and other specific needs of a mouse
behavioural laboratory.
Personnel
Researcher: Natalia Kulesskaya, PhD
Graduate student: Jesse Lindholm, MSc
39
ANNUAL REPORT 2008
40
Mouse Transgenic Unit
www.helsinki.fi/gmmice
Heikki Rauvala
Phone +358 9 191 57621
[email protected]
Mouse transgenic technology has enabled molecular
mechanisms of such complex biological phenomena as
development and behaviour to be studied. In addition,
disease models using mouse transgenics are becoming
increasingly important.
The Transgenic Facility was launched in 1996, and its
first project was to produce overexpressing mice, a project
which has retained its usefulness. Production of knockout
mice using blastocyst injection was established soon after
classical transgenics. Morula aggregation is currently
mainly used for the production of knockout mice.
The Transgenic Unit produces overexpressing and
knockout mice for the projects of several research groups
on the Viikki and Meilahti campuses, both within and
outside the Neuroscience Center. Altogether, about
200 different mouse lines were produced during 19962005. Since Biomedicum on the Meilahti campus now
has its own transgenic facility, the current activity of the
Viikki Unit is mainly directed at meeting the needs of
the research groups on the Viikki campus; the Institute
of Biotechnology and the Neuroscience Center are the
main users of mouse transgenics.
An increasingly evident problem in mouse transgenics
is contamination of imported mouse lines, which prevents
housing in the animal facility and increases the risk of
facility contamination. Therefore, purification of mouse
lines using embryo transfer has been established. In
addition, freezing of mouse embryos is carried out to
ensure back-ups and for long-term storage of mouse lines
that are no longer under active investigation.
By far, the major limiting factor in mouse transgenics
is inadequate capacity in the animal facility, resulting in
the expertise of the Unit not being fully exploited. The
use of spatially and temporally regulated transgenics, in
particular, requires large mouse colonies, and therefore,
sufficient housing facilities. State-of-the art testing
in behavioural studies also requires large numbers of
animals. Building a new animal facility is necessary
before increasing the number of studies using transgenic
mice.
In 2007, the animal facilities of the University,
functioning in several locations, were unified into a single
organization, the Animal Facility of the University of
Helsinki. In this context, the transgenic units have been
unified into one organization, which will start working
in 2009 within the Laboratory Animal Center of the
University of Helsinki.
Personnel
Technicians: Kylli Haller and Raija Ikonen
ANNUAL REPORT 2008
Neuronal Cell Culture Unit
Eero Castrén
Phone +358 9 191 57626
[email protected]
The Neuronal Cell Culture Unit provides the groups in
the Neuroscience Center and other research groups in
the Helsinki region with cultured neurons prepared from
the embryonic rat and mouse hippocampus and cortex.
Centralization of the primary neuronal culture activity is
important in providing continuity and improving quality
and consistency of these cultures. Furthermore, a core
facility saves in expenses by optimizing the use of cells
and centralizing the purchase of culture media, serum
samples, and plasticware.
In addition to the cultures routinely prepared, the unit
can provide cerebellar granule neurons, peripheral ganglia
neurons, and hippocampal slice cultures. The unit has
facilities for transfection and viral transduction of gene
constructs to primary neurons and slice cultures. The
unit also provides cells and trained investigators to other
laboratories and campuses, including the Biomedicum.
Personnel
Technicians: Erja Huttu, Seija Lågas and Outi Nikkilä
41
ANNUAL REPORT 2008
42
Zebrafish Unit
Pertti Panula
Phone +358 9 191 25263
[email protected]
Fast embryonic development, transparent embryos, and
availability of a large number of mutants have rendered
zebrafish one of the favorite models in developmental
biology. Rapidly increasing knowledge of the zebrafish
genome has also enabled efficient identification of
important genes in this species.
Most studies on zebrafish have thus far concentrated
on identifying early developmental phenotypes from
mutation screens. The research carried out at the
Neuroscience Center focuses on new methods utilizing
high-resolution confocal and two-photon imaging
of developing neuronal networks and automated
quantitative behavioural analysis. These methods
are combined with use of translation inhibition with
morpholino oligonucleotides, selection of new mutants
from mutation screens, and studies on mutants produced
with targeted lesions in genomes (TILLING).
One of the goals is to extend efficient phenotype
analysis to a phase in which the central nervous system
produces complex behaviours. Current projects aim
at elucidating the roles of newly identified genes, the
mutations of which produce severe human diseases. In
addition, models of human diseases related to disorders
of the aminergic neuronal systems are being developed.
New mutants from a large mutation screen are also
being characterized. The methods used include gene
cloning and expression analysis, translation inhibition,
developmental analysis using microscopy and gene arrays,
high-resolution imaging, and automated behavioural
techniques. We can currently monitor locomotor activity
and motor behavior of 100 larvae simultaneously. A
battery of behavioral tests is available. The recent addition
of an aquarium space and multiple injection stations have
enabled genetic studies and maintenance of mutant fish
strains to be carried out. The core facility also arranges
practical courses in zebrafish methods, with an emphasis
on neuroscience.
Personnel
Post-doctoral fellows: Yu-Chia Chen, PhD; Maarit HölttäVuori, PhD; Hisaaki Kudo, PhD
Graduate students: Madhusmita Priyadarshini, MSc; Ville
Sallinen, MD; Maria Sundvik, MSc
Technicians: Henri Koivula, BSc; Susanna Norrbacka
ANNUAL REPORT 2008
Neuroscience
Center Research
and Centres of
Excellence
The national strategy for centres of excellence
in research has been jointly developed with
the Academy of Finland and the National
Technology Agency. The centre of excellence
programme is one form of research funding
for promoting the development of creative
research environments. All centres of excellence
in research represent the cutting edge of their
respective fields. Candidates for centres of
excellence include research units or researcher
training units, comprising one or several highquality research teams with shared and clearly
defined research goals, which are at or have
the potential of reaching the international
forefront of their field.
Finnish Centre of Excellence in
Complex Disease Genetics
The group led by Professor Anna-Elina Lehesjoki is one
of the seven research groups forming the Centre of
Excellence in Complex Disease Genetics (CoECDG) of
the Academy of Finland. Research within the Center aims
at dissecting the genetic background of some common
diseases and their trait components by combining special
expertise with the sample resources accessible to center
investigators. The Center builds on accomplishments
of the Centre of Excellence in Disease Genetics of the
Academy of Finland (in 2000-2005), but has a more
extended research program to reflect developments
in the field as well as its own research progress: from
Mendelian diseases to complex traits. The CoECDG
combines diverse expertise of eight group leaders across
institutes in Finland, Sweden, and the UK. The Center was
chosen for funding in the Academy of Finland’s Centre
of Excellence programme in 2006-2011.
Directors of the research teams:
Docent Anu Jalanko (National Institute for Health and
Welfare)
Professor Juha Kere (UH and Karolinska Institutet)
Professor Jaakko Kaprio (UH)
Professor Kimmo Kontula (UH)
Professor Anna-Elina Lehesjoki (UH and Folkhälsan
Institute of Genetics)
Professors Aarno Palotie and Joe Terwilliger (UH and
Sanger Center (AP))
Professor Leena Peltonen-Palotie (National Institute for
Health and Welfare, UH and Sanger Center)
Finnish Centre of Excellence
in Molecular and Integrative
Neuroscience Research
The Board of the Academy of Finland has selected 18
Centres of Excellence to the national CoE programme for
2008-2013 at its meeting on 12 December 2006. The newly
selected CoE in Molecular and Integrative Neuroscience
Research focuses on trophic factors in the mechanisms
of neuronal development, plasticity, and disorders. The
groups of the CoE have complementary expertise in the
fields of molecular/cellular neuroscience, neurophysiology,
neuropharmacology, and systems neuroscience. The aim
is to create a multidisciplinary international CoE in basic
and translational neuroscience.
Directors of the research teams:
Professor Mart Saarma (chairman; Institute of
Biotechnology)
Academy researcher Urmas Arumäe (Institute of
Biotechnology)
Academy researcher Claudio Rivera (Institute of
Biotechnology and Department of Biological and
Environmental Sciences)
Professor Kai Kaila (Department of Biological and
Environmental Sciences and Neuroscience Center)
Professor Heikki Rauvala (Neuroscience Center)
Professor Eero Castrén (Neuroscience Center)
Docent Matti Airaksinen (Neuroscience Center)
43
ANNUAL REPORT 2008
44
Commercialization and Spin-Off Activities:
Founding of Hermo Pharma Ltd.
Henri J. Huttunen, PhD
Acting CEO of Hermo Pharma Ltd.
www.hermopharma.com
Research activity has a high rate of financial return.
By international comparison, the GDP share of R&D
expenditure in Finland is among the highest in the world
(3.47% in 2007). However, only a little over one hundred
private and two public Finnish companies base their
operations on biomedical research. Moreover, success
stories of technology transfer offices of Finnish universities
are rather scarce. The generous governmental investment
in science together with the third legal assignment
of universities call for increased activities regarding
commercialization of academic research in Finland.
The University of Helsinki holds an admirable position
in the global ranking of scientific publications. The
patenting activity in the University ranking equally highly
in the global comparison may be somewhat surprising.
This shows that over the last decade Finnish scientists have
learned to protect their inventions. However, a patented
invention is worthless if it is not licensed out or otherwise
actively commercialized. To enhance commercialization of
academic research in Finland, more efficient technology
transfer, initiative and entrepreneurialism from individual
scientists and an environment that strongly favors spin-off
company activities are needed.
Basic research in the field of neuroscience at
the University of Helsinki has reached a level where
significant, commercially attractive inventions are being
generated in several laboratories. Nevertheless, numerous
unmet medical needs in the field of neurological diseases,
together with an increasing trend for outsourcing
research activities among the marketing pharmaceutical
companies, create an attractive window of opportunity for
small innovative companies with strong R&D pipelines.
In 2006-2008, research groups lead by Professors
Eero Castrén and Heikki Rauvala from the Neuroscience
Center and Professor Mart Saarma from the Institute
of Biotechnology have participated in a specific
commercialization program co-funded by the Finnish
Funding Agency for Technology and Innovation (TEKES).
The goal of this joint activity (“NeuProtec”) was to
increase the value and applicability of academic research
results for industrial utilization. Moreover, identification of
commercialization pathways for select research projects
aimed at paving the way for either licensing these
innovations out or for launching a spin-off company.
In June 2008, the first start-up company closely
associated with the Neuroscience Center was founded.
As a commercialization platform, the main focus of
Hermo Pharma Ltd. is developing novel approaches for
treatment of neurodegenerative diseases and modulation
of neuronal plasticity. The primary target indications for
Hermo Pharma are amblyopia (“lazy eye”), Parkinson’s
disease, and Alzheimer’s disease. To this end, the
company has been building its portfolio of intellectual
property rights based on inventions generated in the
laboratories involved in the NeuProtec commercialization
program. The company plans to carry out the early stages
of preclinical development in close collaboration with the
inventors’ laboratories, facilitating access to key expertise
and the researchers associated with these inventions.
In 2009, Hermo Pharma plans to initiate Phase 2a
clinical studies for treatment of amblyopia in adults. The
lead program, HER-801, focuses on indication expansion
for antidepressants. Professor Eero Castrén s laboratory
has shown that antidepressant drugs have the capacity
ANNUAL REPORT 2008
to restore plasticity in the adult visual cortex, providing
a preclinical proof-of-concept model for treatment of
amblyopia in adults (Maya Vetencourt et al., 2008).
Currently, no treatment is available for amblyopia after
the closure of the critical window of plasticity (by the
age of ~10 years in humans). Yet, amblyopia is the
most common cause of monocular vision loss, with
a prevalence of 2-4% in the general population. The
Parkinson’s and Alzheimer’s programs at Hermo Pharma
are in the preclinical and discovery phases, respectively.
The strength of Hermo Pharma derives from four
critical factors: (1) a strong R&D pipeline with several
projects in different stages of development, (2) a close
collaboration with inventors’ academic laboratories, (3)
a permissive environment generated by the University of
Helsinki and its two institutes, the Neuroscience Center
and the Institute of Biotechnology, and (4) a light cost
structure during the critical early years of operations.
Within the next three to four years, we will be in a position
to evaluate the results of the commercialization program
initiated at the Neuroscience Center.
45
ANNUAL REPORT 2008
46
Administration
engagements are not otherwise regulated or provided for
and authorizes the NC’s agreements unless they require
the approval of the Rector of the University of Helsinki.
The Director of the NC is Professor Heikki Rauvala.
Administration of the Neuroscience Center (NC) is
determined by the Board and the Director. An important
administrative body of the NC is the Scientific Advisory
Board, which promotes the NC’s scientific activities.
Administration Director
The Board
From 18.5.2005 to 30.4.2008, the Board members
were as follows: the Chairman was Professor Matti
Tikkanen (Faculty of Medicine); the Vice-Chairman
was Professor Kielo Haahtela (Faculty of Biosciences);
and members were Professor Markku Kaste (Faculty
of Medicine), Professor Christina Krause (Faculty of
Behavioural Sciences), Professor Pekka Männistö (Faculty
of Pharmacy), Docent Jouni Sirviö (Orion Pharma),
Professor Outi Vainio (Faculty of Veterinary Medicine),
Researcher Juha Knuuttila (personnel representative),
Student Tuuli Lahti (student representative), Master of
Science Tomi Maila (student representative), and Master
of Science Juha Salmi (student representative).
Since 1.5.2008, the Board members have been as
follows: the Chairman is Professor Kielo Haahtela (Faculty
of Biosciences); the Vice-Chairman is Professor Pekka
Männistö (Faculty of Pharmacy); and the members are
Director Antti Haapalinna (Orion Pharma), Professor
Teija Kujala (Faculty of Behavioural Sciences), Professor
Timo Erkinjuntti (Faculty of Medicine), Professor Outi
Vainio (Faculty of Veterinary Medicine), Professor Anu
Wartiovaara (Faculty of Medicine), Student Mikko Berg
(student representative), Student Miia Lehtinen (student
representative), Master of Science Mikael Segerstråle
(student representative) and Master of Science Lauri
Mankki (personnel representative). The Board had four
meetings during the year.
Director
The Director manages and supervises the NC’s activities
and finances, participates in its scientific activities, and
oversees the preparation of matters for discussion by the
Board and the Scientific Advisory Board and the execution
of decisions. The Director also appoints or engages
those members of the NC whose appointments or
The Administration Director is responsible for the NC’s
administration and finances. She also functions as
the NC’s Deputy Director, unless otherwise stated by
the Director with regard to a particular matter. The
Administrative Services Unit and Maintenance personnel
are subject to the authority of the Administration Director.
The Administration Director of the NC is Anna Mattila,
MSc.
Scientific Advisory Board
The NC has a Scientific Advisory Board that consists of
international members. This Board promotes the NC’s
scientific activities, issues statements on the competence
of applicants for the post of Director and the posts or
duties of Research Directors, evaluates the NC’s scientific
programs, formulates initiatives, and provides statements
on new research programs.
The Scientific Advisory Board comprises a minimum of
five and a maximum of ten distinguished researchers from
Finland or abroad in the scientific fields represented by
the NC. The Rector of the University of Helsinki appoints
the members of the Board for a five-year term based on
the proposal of the Board of Trustees.
Currently, the Scientific Advisory Board consists of
the following members:
Chairman: Professor Heikki Ruskoaho (Faculty of
Medicine, University of Oulu)
Members: Professor Anders Björklund (Wallenberg
Neuroscience Center, Lund University, Sweden)
Professor Barry J. Everitt (Dept. of Experimental
Psychology, University of Cambridge, UK)
Professor Freda Miller (Dept. of Molecular Genetics,
University of Toronto, Canada)
Professor Ole P. Ottersen (Faculty of Medicine, University
of Oslo, Norway)
Professor Thomas Perlmann (Ludwig Institute for Cancer
Research, Karolinska Institute, Sweden)
Dr. Geneviève Rougon, Directeur (Institut de Biologie du
Développement de Marseille [IBDM], Marseille, France)
ANNUAL REPORT 2008
Publications 2008
1. Anttonen, A., and Lehesjoki, A.-E. (2008).
Genetiskt betingade barndomsepilepsier. Finska
Läkaresällskapets Handlingar 168 (2): 32-38.
2. Anttonen, A.K., Siintola, E., Tranebjaerg, L.,
Iwata, N.K., Bijlsma, E.K., Meguro, H., Ichikawa, Y., Goto,
J., Kopra, O., and Lehesjoki, A.E. (2008). Novel SIL1
mutations and exclusion of functional candidate genes in
Marinesco-Sjögren syndrome. Eur. J. Hum. Genet. 16(8):
961-969.
3. Blaesse, P., Airaksinen, M.S., Rivera, C., and Kaila,
K. (2008). Cation-chloride cotransporters and neuronal
function. Neuron, invited review, in press.
4. Castrén, E., and Rantamäki, T. (2008).
Neurotrophins in depression and antidepressant effects.
Novartis Found Symp. 289: 43-52; discussion 53-59, 8793.
5. Colonnese, M.T., Phillips, M.A., ConstantinePaton, M., Kaila, K., and Jasanoff, A. (2008). Development
of hemodynamic responses and functional connectivity in
rat somatosensory cortex. Nat. Neurosci. 11(1): 72-79.
6. Fritchie, K., Siintola, E., Armao, D., Lehesjoki,
A.-E., Marino, T., Powell, C., Tennison, M., Booker,
J.M., Koch, S., Partanen, S., Suzuki, K., Tyynelä, J.,
and Thorne, L.B. (2008). Novel mutation and the first
prenatal screening of cathepsin D deficiency (CLN10).
Acta Neuropathol., Epub ahead of print Sep 2.
7. Greco, D., Somervuo, P., Di Lieto, A., Raitila, T.,
Nitsch, L., Castrén, E., and Auvinen, P. (2008). Physiology,
pathology and relatedness of human tissues from gene
expression meta-analysis. PLoS ONE 3(4): e1880.
8. Hämäläinen, R., Karlberg, N., Kallijärvi, J.,
Lipsanen-Nyman, M., and Lehesjoki, A.-E. (2008). TRIM37
and mulibrey nanism. In: Inborn Errors of Metabolism,
Eds. Epstein, C.J., Erickson, R.P., and Wynshaw-Boris,
A. 2nd edition, pp. 1540-1543. Oxford University Press,
Oxford.
9. Hämäläinen, R., Lehesjoki, A.-E., and LipsanenNyman, M. (2008). Mulibrey nanism. In: Encyclopedia of
Molecular Mechanisms of Disease, Ed. Lang, F. SpringerVerlag, Berlin, Heidelberg, in press.
10. Hölttä-Vuori, M., Uronen, R.-L., Repakova, J.,
Salonen, E., Vattulainen, I., Panula, P., Li, Z., Bittman, R.,
and Ikonen, E. (2008). BODIPY-cholesterol: A new tool
to visualize sterol trafficking in living cells and organisms.
Traffic 9: 1839-1849.
11. Ilmakunnas, M., Tukiainen, E.M., Rouhiainen,
A., Rauvala, H., Arola, J., Nordin, A., Mäkisalo, H.,
Höckerstedt, K., and Isoniemi, H. (2008). High mobility
group box 1 protein as a marker of hepatocellular injury
in human liver transplantation. Liver Transpl. 14(10):
1517-1525.
12. Joensuu, T., Lehesjoki, A.-E., and Kopra, O.
(2008). Molecular background of EPM1-UnverrichtLundborg disease. Epilepsia 49(4): 557-563.
13. Kaila, K., Blaesse, P., and Sipilä, S.T. (2008).
Development of GABAergic signaling: from molecules
to emerging networks. In: Oxford Handbook of
Developmental Behavioral Neuroscience, Eds. Blumberg,
M.S., Freeman, J.H., and Robinson, S.R. Oxford University
Press, Oxford, in press.
14. Karpova, N.N., Lindholm, J., Pruunsild, P.,
Timmusk, T., and Castrén, E. (2008). Long-lasting
behavioural and molecular alterations induced by
early postnatal fluoxetine exposure are restored
by chronic fluoxetine treatment in adult mice. Eur.
Neuropsychopharmacol., Epub ahead of print Oct 28.
15. Khirug, S., Yamada, J., Afzalov, R., Voipio,
J., Khiroug, L., and Kaila, K. (2008). GABAergic
depolarization of the axon initial segment in cortical
principal neurons is caused by the Na-K-2Cl cotransporter
NKCC1. J. Neurosci. 28(18): 4635-4639.
16. Kousi, M., Siintola, E., Dvorakova, L., Vlaskova,
H., Turnbull, J., Topcu, M., Yuksel, D., Gokben, S.,
Minassian, B., Elleder, M., Mole, S., and Lehesjoki, A.-E.
(2008). Mutations in CLN7/MFSD8 are a common cause
of variant late-infantile neuronal ceroid lipofuscinosis.
Brain, in press.
17. Kudo, H., Liu, J., Jansen, E.J., Ozawa, A., Panula,
P., Martens, G.J., and Lindberg, I. (2008). Identification of
proSAAS homologs in lower vertebrates: Conservation of
hydrophobic helices and convertase-inhibiting sequences.
Endocrinology, Epub ahead of print Oct 23.
18. Leo, J.C., Elovaara, H., Brodsky, B., Skurnik,
M., and Goldman, A. (2008). The Yersinia adhesin YadA
binds to a collagenous triple-helical conformation but
47
48
ANNUAL REPORT 2008
without sequence specificity. Protein Eng. Des. Sel. 21(8):
475-484.
19. Lyly, A., Marjavaara, S.K., Kyttälä, A., Uusi-Rauva,
K., Luiro, K., Kopra, O., Martinez, L.O., Tanhuanpää, K.,
Kalkkinen, N., Suomalainen, A., Jauhiainen, M., and
Jalanko, A. (2008). Deficiency of the INCL protein Ppt1
results in changes in ectopic F1-ATP synthase and altered
cholesterol metabolism. Hum. Mol. Genet. 17(10): 14061417.
20. Markkanen, M., Uvarov, P., and Airaksinen,
M.S. (2008). Role of upstream stimulating factors in the
transcriptional regulation of the neuron-specific K-Cl
cotransporter KCC2. Brain Res. 1236: 8-15.
21. Martin, M.G., Perga, S., Trovò, L., Rasola, A.,
Holm, P., Rantamäki, T., Harkany, T., Castrén, E., Chiara,
F., and Dotti, C.G. (2008). Cholesterol Loss Enhances TrkB
Signaling in Hippocampal Neurons Aging in Vitro. Mol.
Biol. Cell 19(5): 2101-2112.
22. Maya Vetencourt, J.F., Sale, A., Viegi, A.,
Baroncelli, L., De Pasquale, R., O’Leary, O.F., Castrén,
E., and Maffei, L. (2008). The antidepressant fluoxetine
restores plasticity in the adult visual cortex. Science
320(5874): 385-388.
23. Monto, S., Palva, S., Voipio, J., and Palva, J.M.
(2008). Very slow EEG fluctuations predict the dynamics
of stimulus detection and oscillation amplitudes in
humans. J. Neurosci. 28(33): 8268-8272.
24. O’Leary, O.F., Wu, X., and Castren, E. (2008).
Chronic fluoxetine treatment increases expression of
synaptic proteins in the hippocampus of the ovariectomized
rat: Role of BDNF signalling. Psychoneuroendocrinology,
Epub ahead of print Oct 31.
25. Onishchenko, N., Karpova, N., Sabri, F., Castrén,
E., and Ceccatelli, S. (2008). Long-lasting depression-like
behavior and epigenetic changes of BDNF gene expression
induced by perinatal exposure to methylmercury. J.
Neurochem. 106(3): 1378-1387.
26. Paavilainen, V.O., Oksanen, E., Goldman,
A., and Lappalainen, P. (2008). Structure of the actindepolymerizing factor homology domain in complex with
actin. J. Cell Biol. 182(1): 51-59.
27. Papp, E., Rivera, C., Kaila, K., and Freund, T.F.
(2008). Relationship between neuronal vulnerability and
potassium-chloride cotransporter 2 immunoreactivity
in hippocampus following transient forebrain ischemia.
Neuroscience 154(2): 677-689.
28. Parkash, V., Leppänen, V.-M., Virtanen,
H., Jurvansuu, J.M., Bespalov, M.M., Sidorova, Y.A.,
Runeberg-Roos, P., Saarma, M., and Goldman, A. (2008).
The Structure of the GDNF2-GFRα12 complex: Insights
into RET signalling and Heparin binding. J. Biol. Chem.
283: 35164-35172.
29. Patana, A.S., Kurkela, M., Finel, M., and
Goldman, A. (2008). Mutation analysis in UGT1A9
suggests a relationship between substrate and catalytic
residues in UDP-glucuronosyltransferases. Protein Eng.
Des. Sel. 21(9): 537-543.
30. Paveliev, M., Hienola, A., Jokitalo, E., Planken,
A., Bespalov, M.M., Rauvala, H., and Saarma, M. (2008).
Sensory neurons from N-syndecan-deficient mice are
defective in survival. Neuroreport 19(14): 1397-1400.
31. Pryazhnikov, E., and Khiroug, L. (2008). Submicromolar increase in [Ca2+]i triggers delayed exocytosis
of ATP in cultured astrocytes. Glia 56(1): 38-49.
32. Rantamäki, T., and Castrén, E. (2008). Targeting
TrkB neurotrophin receptor to treat depression. Expert
Opin. Ther. Targets 12(6): 705-715.
33. Riekki, R., Pavlov, I., Tornberg, J., Lauri, S.E.,
Airaksinen, M.S., and Taira, T. (2008). Altered synaptic
dynamics and hippocampal excitability but normal longterm plasticity in mice lacking hyperpolarizing GABA A
receptor-mediated inhibition in CA1 pyramidal neurons.
J. Neurophysiol. 99(6): 3075-3089.
34. Saarikangas, J., Hakanen, J., Mattila, P.K.,
Grumet, M., Salminen, M., and Lappalainen, P. (2008).
ABBA regulates plasma-membrane and actin dynamics
to promote radial glia extension. J. Cell Sci. 121(Pt 9):
1444-1454.
35. Sallinen, V., Torkko, V., Sundvik, M., Reenilä, I.,
Khrustalyov, D., Kaslin, J., and Panula, P. (2008). MPTP
and MPP+ target specific aminergic cell populations in
larval zebrafish. J. Neurochem., Epub ahead of print Nov
27.
36. Schuchmann, S., Tolner, E.A., Marshall,
P., Vanhatalo, S., and Kaila, K. (2008). Pronounced
increase in breathing rate in the “hair dryer model” of
experimental febrile seizures. Epilepsia 49(5): 926-928.
37. Schuchmann, S., Vanhatalo, S., and Kaila, K.
(2008). Neurobiological and physiological mechanisms
of fever-related epileptiform syndromes. Review. Brain
Dev., in press.
ANNUAL REPORT 2008
38. Shulga, A., Thomas-Crusells, J., Sigl, T., Blaesse,
A., Mestres, P., Meyer, M., Yan, Q., Kaila, K., Saarma,
M., Rivera, C., and Giehl, K.M. (2008). Posttraumatic
GABA(A)-mediated [Ca2+]i increase is essential for the
induction of brain-derived neurotrophic factor-dependent
survival of mature central neurons. J. Neurosci. 28(27):
6996-7005.
39. Sipilä, S.T., and Kaila, K. (2008). GABAergic
control of CA3-driven network events in the developing
hippocampus. In: Inhibitory Regulation of Excitatory
Neurotransmission, Ed. Darlison, M. Results and problems
in cell differentiation 44: 99-121. Springer Verlag, Berlin,
Heidelberg.
40. Tervonen, T.A., Louhivuori, V., Sun, X.,
Hokkanen, M.E., Kratochwil, C.F., Zebryk, P., Castrén,
E., and Castrén, M.L. (2008). Aberrant differentiation
of glutamatergic cells in neocortex of mouse model for
fragile X syndrome. Neurobiol. Dis., Epub ahead of print
Nov 6.
41. Tian, L., Lappalainen, J., Autero, M., Hänninen,
S., Rauvala, H., and Gahmberg, C.G. (2008). Shedded
neuronal ICAM-5 suppresses T-cell activation. Blood
111(7): 3615-3625.
42. Uusi-Rauva, K., Luiro, K., Tanhuanpää, K.,
Kopra, O., Martín-Vasallo, P., Kyttälä, A., and Jalanko,
A. (2008). Novel interactions of CLN3 protein link Batten
disease to dysregulation of fodrin-Na(+), K(+) ATPase
complex. Exp. Cell Res. 314(15): 2895-2905.
43. Vanhatalo, S., and Kaila, K. (2008). Emergence
of spontaneous and evoked EEG activity in the human
brain. In: The Newborn Brain: Neuroscience and Clinical
Applications, Eds. Lagercrantz, H., Hanson, M., Evrard,
P., and Rod, C. 2nd edition. Cambridge University Press,
Cambridge, in press.
44. Vanhatalo, S., and Kaila, K. (2008). Generation
of ‘positive slow waves’ in the preterm EEG: by the brain
or by the EEG setup? Clin. Neurophysiol. 119(6): 14531454; author reply 1454-1455.
45. Vanhatalo, S., Voipio, J., and Kaila, K. (2008).
Infraslow EEG activity. In: Electroencephalography: Basic
Principles, Clinical Applications, and Related Fields,
Eds. Niedermeyer, E., and Lopes da Silva, F. 6th edition,
pp. 489-493. Williams&Wilkins, Baltimore-Munich, in
press.
46. von Schantz, C., Saharinen, J., Kopra, O.,
Cooper, J.D., Gentile, M., Hovatta, I., Peltonen, L., and
Jalanko, A. (2008). Brain gene expression profiles of Cln1
and Cln5 deficient mice unravels common molecular
pathways underlying neuronal degeneration in NCL
diseases. BMC Genomics 9: 146.
47. Weber, Y.G., Serratosa, J.M., and Lehesjoki, A.E. (2008). Unverricht-Lundborg Disease. In: Encyclopedia
of Molecular Mechanisms of Disease, Ed. Lang, F.
Springer-Verlag, Berlin, Heidelberg, in press.
48. Xiong, Y., Patana, A.S., Miley, M.J., Zielinska,
A.K., Bratton, S.M., Miller, G.P., Goldman, A., Finel, M.,
Redinbo, M.R., and Radominska-Pandya, A. (2008).
The first aspartic acid of the DQxD motif for human
UDP-glucuronosyltransferase 1A10 interacts with UDPglucuronic acid during catalysis. Drug Metab. Dispos.
36(3): 517-522.
49. Zylka, M.J., Sowa, N.A., Taylor-Blake, B.,
Twomey, M.A., Herrala, A., Voikar, V., and Vihko, P.
(2008). Prostatic acid phosphatase is an ectonucleotidase
and suppresses pain by generating adenosine. Neuron
60(1): 111-122.
49
ANNUAL REPORT 2008
50
Theses 2008
Doctoral Theses
Master’s Theses
Anttonen, Anna-Kaisa. The molecular basis of
Marinesco-Sjögren syndrome
Rouhiainen, Ari. Role of HMGB1 in cells of the
circulation
Siintola, Eija. Identification of two novel human
neuronal ceroid lipofuscinosis genes
Tervonen, Topi. Differentiation of neural stem cells in
fragile X syndrome
Ahonen, Erika. SCN2A mutations in Finnish patients
with childhood onset intractable epilepsy
Autio, Henri. Glutamaatin NMDA-reseptorin salpaajien
masennuslääkkeen kaltaiset vaikutukset
Heinonen, Mirja. GDNF and GFRαs signalling in frog
cardiac ganglion
Mankki, Lauri. Syndekaani-3:n vaikutus BACE1:n
aktiivisuuteen
51
ANNUAL REPORT 2008
Finances
Funding of the Neuroscience Center in 2008
In euros
Percentage
1. Basic funding
University of Helsinki (own assets)
University of Helsinki and Ministry of Education
2. Competitive funding
Academy of Finland
Sigrid Jusélius Foundation
Folkhälsan
Graduate schools
University of Helsinki
European Union
Biocentrum Helsinki
Other science organizations
Performance-based funding
Others
Total
2 314 000
1 200 000
1 114 500
3 550 099
1 309 280
669 500
371 811
277 449
215 000
191 000
158 926
144 033
143 500
69 600
5 864 099
39.5%
20.5%
19.0%
60.5%
22.3%
11.4%
6.3%
4.7%
3.7%
3.3%
2.7%
2.5%
2.4%
1.2%
100%
Proportion of the Financiers of the Total Funding in 2008
9%
Academy of Finland
23 %
3%
4%
University of Helsinki (own assests)
5%
University of Helsinki and Ministry of Education
Sigrid Jusélius Foundation
6%
Folkhälsan
20 %
Graduate schools
11 %
University of Helsinki
19 %
European Union
Others
ANNUAL REPORT 2008
52
Staff
Personnel in 2008
Researchers
- PhDs
- Graduate students
Undergraduate students
Laboratory technicians
Administration
Maintenance
Total
* person-years
Number
%
PY*
95
73.6
81
%
76
15
14
4
1
129
11.6
10.9
3.1
0.8
100
7
14
4
1
106
7
13
3
1
100
49
46
Proportion of foreign researchers in the category of Researchers
Proportion of PhDs in the category of Researchers
Proportion of women in the categories Researchers and Undergraduate students
Proportion of women of all staff
42.7%
51.6%
47.3%
52.7%
Proportion of Staff Categories (percentage in person-years) in 2008
13 %
3%
1%
7%
Researchers
Undergraduate students
Laboratory technicians
A Administration
Maintenance
76 %
53
ANNUAL REPORT 2008
Personnel in 2008
Group leaders
Airaksinen, Matti, MD, PhD
Castrén, Eero, MD, PhD
Kaila, Kai, PhD
Khirug, Leonard, PhD
Lehesjoki, Anna-Elina, MD, PhD
Panula, Pertti, MD, PhD
Rauvala, Heikki, MD, PhD
Taira, Tomi, PhD
Adjunct professors
Goldman, Adrian, PhD
Kere, Juha, MD, PhD
Lappalainen, Pekka, PhD
Tanila, Heikki, MD, PhD
Project leaders
Huttunen, Henri, PhD **
Lauri, Sari, PhD
Palva, Matias, PhD
Kudo, Hisaaki, PhD
Kulesskaya, Natalia, PhD
Lahtinen, Ulla, PhD
Lyubimov, Yaroslav, PhD **
Molchanova, Svetlana, PhD
Nuutinen, Saara, PhD
O’Leary, Olivia, PhD **
Palva, Satu, PhD
Paveliev, Mikhail, PhD **
Polvi, Anne, PhD
Pryazhnikov, Evgeny, MD, PhD
Rantamäki, Tomi, PhD (pharm)
Rouhiainen, Ari, PhD
Ruusuvuori, Eva, PhD
Savelyev, Sergey, PhD **
Siintola, Eija, PhD **
Sipilä, Sampsa, PhD **
Tian, Li, PhD
Tiraboschi, Ettore, PhD
Tolner, Else, PhD
Valli-Jaakola, Kaisa, PhD **
Wegelius, Katri, PhD
Wu, Xuefei, PhD
Post-doctoral fellows
Afzalov, Ramil, PhD
Anthoni, Heidi, PhD **
Anttonen, Anna-Kaisa, MD, PhD
Aula-Kahanpää, Nina, PhD
Blaesse, Peter, PhD
Chen, Yu-Chia, PhD
Clarke, Vernon, PhD **
Di Lieto, Antonio, MD, PhD
Joensuu, Tarja, PhD
Karlstedt, Kaj, PhD
Karpova, Nina, PhD
Khrustalyov, Denis, PhD **
Koch, Sabine, PhD **
Kolikova, Julia, PhD
Kopra, Outi, PhD
Kremneva, Elena, PhD
Graduate students
Ahmad, Faraz, MSc **
Anttonen, Anna-Kaisa, MD
(PhD defence 8.2.2008)
Autio, Henri, MSc (pharm) **
Gransalke, Kathleen, MSc
Helmy, Mohamed, MB, BCh **
Hokkanen, Marie-Estelle, MSc
Huttu, Kristiina, MSc **
Huupponen, Johanna, MSc **
Juuri, Juuso, MSc
Kaisler, Raphaela, MSc **
Khirug, Stanislav, MSc
Kiiltomäki, Marjaana, MSc
Kirilkin, Ilya, MD
Knuuttila, Juha, MSc
Kousi, Maria, MSc
Kuja-Panula, Juha, MSc
Kulashekhar, Shrikanth, BSc
Kulesskiy, Evgeny, MSc
Kupari, Jussi, MSc
Kuronen, Mervi, MSc
Laakso, Tiina, MSc
Laari, Anni, MSc **
Lindholm, Jesse, MSc (pharm)
Maila, Tomi, MSc **
Mankki, Lauri, MSc
Manninen, Otto, MSc
Marabelli, Alessandro, MSc
Markkanen, Marika, MSc
Molotkov, Dmitry **
Monto, Simo, MSc (Tech)
Määttänen, Ilmari, MSc **
Paveliev, Mikhail, MSc **
(PhD defence 12.12.2008)
Priyadarshini, Madhusmita, MSc
Rouhiainen, Ari, MSc
(PhD defence 8.8.2008)
Rozov, Stanislav, MSc
Ruusuvuori, Eva, MSc
(PhD defence 28.11.2008)
Sallert, Marko, MSc
Sallinen, Ville, MD
Segerstråle, Mikael, MSc
Sharma, Vikram **
Siintola, Eija, MSc **
(PhD defence 16.5.2008)
Sirén, Auli, MD **
Sundvik, Maria, MSc
Tegelberg, Saara, MSc
Tervonen, Topi, MSc **
(PhD defence 2.2.2008)
Uvarov, Pavel, MSc
Vanttola, Päivi, MSc
Vesikansa, Aino, MSc
Yukin, Alexey, MSc
Zhao, Xiang, MSc
ANNUAL REPORT 2008
54
Undergraduate students
Autio, Henri
Dugan, Artjom **
Kysenius, Kai **
Mattila, Katariina, BM **
Nykänen, Niko-Petteri **
Ojala, Tiia
Pousi, Suvi **
Puskarjov, Martin **
Rouhinen, Santeri, BSc **
Sakha, Prasanna **
Sundelin, Lotta
Talvitie, Minnamari, BSc **
Tilli, Elizaveta **
Toleikyté, Gabija **
Vesa, Liisa
Östman, Annika **
Technicians and other
technical staff
Ahde, Kirsi
Aronen, Mira **
Berg, Kaija
Hakala, Paula
Haller, Kylli
Hellgrén, Hanna
Huttu, Erja
Ikonen, Raija
Koivula, Henri, BSc
Lehtonen, Anna, BSc
Lågas, Seija
Nikkilä, Outi
Norrbacka, Susanna
Pauloff, Hanna **
Saarikalle, Eeva-Liisa
Toivonen, Teija-Tuulia
Träskelin, Ann-Liz **
Administrative services
unit and maintenance
Duus, Markus
Mattila, Anna, MSc
Maunula, Minna, MSc
Rosenblad, Tarja
Other staff
Laakkonen, Liisa, PhD
Lahtinen, Ulla, PhD
Vainio, Ilari, PhD **
** working part of the year
Yliopistopaino 2009