REVIEW
B. Hutcheon and Y. Yarom – Frequency preferences of neurons
Selected references
Acknowledgements
The authors’
research was
supported
by The Israel
Science Foundation
and The European
Commision.
1 Steriade, M. et al. (1990) Thalamic Oscillations and Signalling, John
Wiley and Sons
2 Traub, R.D. and Miles, R. (1991) Neuronal Networks of the
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Calcium signaling in the ER: its role in
neuronal plasticity and neurodegenerative
disorders
Mark P. Mattson
and Sic L. Chan
are at the
Laboratory of
Neurosciences,
National Institute
on Aging,
Baltimore, MD
21224, USA.
Frank M. LaFerla
and Malcolm A.
Leissring are at the
Laboratory of
Molecular Neuropathogenesis, Dept
of Neurobiology
and Behavior,
University of
California at Irvine,
CA 92697, USA.
P. Nickolas Shepel
and Jonathan D.
Geiger are at
the Dept of
Pharmacology
and Therapeutics,
University of
Manitoba Faculty
of Medicine,
Winnipeg,
Manitoba, Canada.
222
Mark P. Mattson, Frank M. LaFerla, Sic L. Chan, Malcolm A. Leissring, P. Nickolas Shepel
and Jonathan D. Geiger
Endoplasmic reticulum (ER) is a multifaceted organelle that regulates protein synthesis and
trafficking, cellular responses to stress, and intracellular Ca21 levels. In neurons, it is distributed
between the cellular compartments that regulate plasticity and survival, which include axons,
dendrites, growth cones and synaptic terminals. Intriguing communication networks between ER,
mitochondria and plasma membrane are being revealed that provide mechanisms for the precise
regulation of temporal and spatial aspects of Ca21 signaling. Alterations in Ca21 homeostasis in
ER contribute to neuronal apoptosis and excitotoxicity, and are being linked to the pathogenesis
of several different neurodegenerative disorders, including Alzheimer’s disease and stroke.
Trends Neurosci. (2000) 23, 222–229
E
NDOPLASMIC RETICULUM (ER) is widely distributed
within neurons, being present in dendrites and dendritic spines, axons and presynaptic nerve terminals,
and in growth cones (Fig. 1)1–5. It is highly motile, rapidly
extending into and retracting from distal regions of
growth cones5, and congregating in stack-like structures
within dendrites in response to stimulation of metabotropic glutamate receptors6. Microtubules and actin
filaments appear to have key roles in controlling ER
motility, as well as in its structure and function7,8. ER
is continuous with the outer nuclear membrane and is
often associated intimately with plasma membrane and
mitochondria, which suggests functional coupling beTINS Vol. 23, No. 5, 2000
tween these structures9. It is classically divided into two
subtypes: ‘rough’ ER, which contains ribosomes and is
responsible for protein synthesis, and ‘smooth’ ER,
which can serve a particularly important role in Ca21
signaling. Although smooth and rough ER coexist in
neuronal cell bodies and proximal regions of axons and
dendrites, the specialized endings of neurites (growth
cones, axon terminals and dendritic spines) contain
mainly smooth ER. Emerging evidence suggests that,
by controlling levels of cytoplasmic free Ca21 locally in
growth cones and synaptic compartments, ER regulates
functional and structural changes in nerve cell circuits
in both the developing and adult nervous systems.
0166-2236/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0166-2236(00)01548-4
REVIEW
M.P. Mattson et al. – Ca21 signaling in the ER
ER Ca21 signaling
(a)
TINS Vol. 23, No. 5, 2000
223
Fraction 5
Fraction 4
Fraction 3
Fraction 2
Fraction 1
Synaptosomes
[3H]Ryanodine bound
(fmoles/mg protein)
Several proteins are housed in
RyR
IP3R
the ER that control movements of
Ca21 across its membrane under
basal conditions and in response to
environmental stimuli10. Under
resting conditions the concentration
of Ca21 in the ER lumen is considerably higher (10–100 mM) than the
Ca21 concentration in the cytoplasm
(100–300 nM). This Ca21 gradient is
maintained by an ATP-dependent
pump called SERCA (smooth ER
Ca21 ATPase) in the ER membrane
(Fig. 2a). ER also contains two types
of Ca21 channel, inositol (1,4,5)trisphosphate receptors (IP3Rs) and
(c)
ryanodine receptors (RyRs), which (b)
40
provide conduits for the rapid re21
lease of Ca . Different ‘pools’ of
30
ER Ca21 might exist that contain
either IP3Rs, RyRs, or both (Fig. 2a).
20
Calcium is released from IP3R-containing pools in response to ag10
onists that activate receptors coupled, via a GTP-binding protein, to
0
phospholipase C (PLC). Activation
of PLC results in cleavage of
PtdIns(4,5)P2, which results in the
liberation of diacylglycerol and
Ins(1,4,5)P3. Ins(1,4,5)P3 binds to
the IP3Rs in the ER, which results
trends in Neurosciences
in channel opening. Calcium can be
released from IP3R-regulated pools Fig. 1. Subcellular localization and structure–function features of endoplasmic reticulum in neurons. (a) Immunoreceptor (RyR) and the IP31 receptor in embryonic rat hippovia a positive-feedback mechanism reactivity with antibodies against the type 2 ryanodine
21
campal
neurons
in
cell
culture.
Both
types
of
Ca
release
channels in the endoplasmic reticulum (ER) are distributed
21
21
called Ca -induced Ca release, alwithin growing neurites of the cells. Color scale bar indicates relative levels of immunoreactivity. (b) Electron micrograph
though more typically this mechashowing synapses in region CA1 of hippocampus of an adult mouse. ER is present in both presynaptic terminals and
nism has been linked with RyRs. postsynaptic dendrites. (c) Synaptosomal subfractions were prepared and levels of RyRs quantified. RyRs were more
IP3Rs and RyRs are found in over- abundant in the lightest fractions (1–3), which contain synaptic vesicles, compared with intact synaptosomes or with
lapping populations of neurons the heavier fractions (4 and 5), which lack vesicles. Scale bars, 5mm in (a) and 100nm in (b).
throughout the nervous system,
but also exhibit clear differences in
relative levels and in subcellular localization. RyRs are
Calcium release from, and possibly Ca21 uptake into,
present at particularly high levels in olfactory bulb ER is regulated by a complex array of modulatory proand in subregions of the hippocampus, whereas levels teins and inter-organellar signals. Proteins that have
of IP3Rs are highest in cerebellar Purkinje cells and CA1 been shown to modulate Ca21 release from ER, apparhippocampal neurons11. Within the hippocampus, ently by direct interaction with either IP3Rs or RyRs,
levels of RyRs are particularly high in the dentate gyrus include FKBP (FK506 binding protein; a 12 kDa cytoand CA3 pyramidal neurons11,12. Although IP3Rs are solic protein associated with RyR – the receptor for the
mostly found in dendritic shafts and cell bodies, levels immunosuppressant drugs, FK506 and rapamycin19,20);
of RyRs are highest in axons and dendritic spines. the protein phosphatase calcineurin, which interacts
Indeed, it has been shown using autoradiography and with IP3Rs (Ref. 21); the Ca21-binding protein, calmodulesioning12, as well as subcellular fractionation tech- lin, which modifies IP3R activity22; ankyrin, a cytoskelniques13–15, that high levels of RyRs are associated with eton-associated protein that might link actin filaments
synaptosomes and synaptosomal subfractions contain- with ER (Ref. 23); sorcin, a 22 kDa RyR-associated Ca21ing synaptic vesicles (Fig. 1). The presence of caffeine- binding protein found in neurons throughout the
sensitive Ca21 stores (presumed ryanodine sensitive) in brain24; and presenilin 1, a 49 kDa integral membrane
presynaptic nerve terminals, together with the possi- protein in the ER that interacts with the RyR and has a
bility that neurotransmitter release might be triggered role in the pathogenesis of Alzheimer’s disease25. It has
by Ca21 released through intraterminal RyRs, suggests become clear in recent years that ER can respond to,
that ER has a central role in the control of neurotrans- and modify the function of, Ca21-regulatory systems in
mitter release16–18. Thus, ryanodine- and Ins(1,4,5)P3- the plasma membrane and mitochondria. In addition
sensitive ER Ca21 pools might subserve complementary to the well-described Ins(1,4,5)P3-mediated Ca21-release
roles. Knowledge of the pharmacology of ER Ca21-store pathway activated by plasma membrane receptors
regulation is rapidly growing, and is providing an array linked to PtdIns hydrolysis10, ER Ca21 release can modify
of experimental tools to manipulate ER Ca21 uptake Ca21 influx through voltage-dependent channels in
and release (Table 1).
the plasma membrane, as described by Chavis and
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M.P. Mattson et al. – Ca21 signaling in the ER
Glutamate
(a)
(b)
Ca2+
VDCC
MR
PLC
Saline
Thapsigargin (100 nM)
Caffeine (2 mM)
Glutamate (50 µM)
Xestospongin (1 µM)
Xestospongin + Glutamate
GP
PMCA
+
ATP
Ins(1,4,5)P3
Mitochondria
Ca2+
Ca2+
RyR
PS
FKBP
PS
ER
Ca2+
25
15
5
Ca2+
Ca2+
SERCA
–5
Ca2+
Axons
(c)
Low [Ins(1,4,5)P3]
Outgrowth rate (µm/hr)
35
= Ins(1,4,5)P3
Intermediate [Ins(1,4,5)P3]
Blip
Dendrites
High [Ins(1,4,5)P3]
Puff
Wave
Cytosol
Lumen
Endoplasmic reticulum
Ca2+
trends in Neurosciences
21
21
Fig. 2. Regulation and functions of ER-mediated Ca release. (a) Mechanisms of Ca regulation in the endoplasmic reticulum (ER), and interactions with plasma membrane and mitochondrial Ca21-regulating systems. (b) Outgrowth rates of axons and dendrites were quantified in cultured
embyronic hippocampal pyramidal neurons (beginning at three days in culture) over 24 h after exposure to the indicated treatments. Values are
the mean and SD (three cultures; 10–12 neurons assessed/culture). (c) Ca21 releasefrom the ER is quantal in nature. High-resolution microscopy
has revealed the existence of discrete Ca21-release events. ‘Blips’ are believed to represent the activity of single IP3R and can occur spontaneously or
in the presence of low levels of Ins(1,4,5)P3 (left). ‘Puffs’ are triggered by intermediate levels of Ins(1,4,5)P3 and are due to the activity of functionally associated groups of IP3R (middle). At high Ins(1,4,5)P3 concentrations, neighboring Ca21 puffs are activated that can propagate along the
ER as a Ca21 ‘wave’ (right). Abbreviations: FKBP, FK-506 binding protein; GP, GTP-binding protein; MR, membrane receptor; PLC, phospholipase C;
PMCA, plasma membrane Ca21 ATPase; PS, presenilin; RyR, ryanodine receptor; SERCA, smooth endoplasmic reticulum Ca21 ATPase; VDCC, voltagedependent Ca21 channel.
coworkers26. Recent studies have demonstrated intriguing functional relationships between Ca21 release from
Ins(1,4,5)P3-sensitive ER stores and mitochondrial
Ca21 uptake. Mitochondria in close physical proximity
to ER rapidly take up Ca21 released from ER such that
local cytoplasmic Ca21 levels in the ER–mitochondria
cleft are markedly higher than global increases in cytoplasmic Ca21 concentration9,27. Interestingly, mitochondrial Ca21 uptake is stimulated by ER-mediated
Ca21 release only when the release is induced in a pulsatile manner, and not when levels of Ins(1,4,5)P3 are
gradually increased. These data, and other morphological findings9, suggest that mitochondrial uptake sites
might be concentrated in regions of the membrane
apposed to IP3R-containing ER.
Periodic oscillations of cytosolic Ca21 levels are
believed to have important roles in various metabolic
and signaling processes in many cell types, including
neurons. Reciprocal interactions between ER Ca21 stores,
mitochondria and plasma membrane Ca21 channels
appear to be required for Ca21 oscillations28,29. Accordingly, manipulations that stimulate or suppress ERmediated Ca21 release can either induce or prevent Ca21
224
TINS Vol. 23, No. 5, 2000
oscillations in neurons30. Calreticulin, an ER-resident
Ca21-binding protein, can modulate Ca21 oscillations
by regulating the activity of SERCA proteins31. Recent
findings suggest that both calreticulin-containing ER
and mitochondria are located at sites of Ca21-wave
regeneration in astrocytes32, suggesting that the mechanisms controlling Ca21 oscillations and Ca21 waves are
very similar. Glial Ca21 waves controlled by ER might
also communicate signals to neurons; for example, studies of embryonic rat hippocampal neurons growing on
an astrocyte monolayer have shown that blockade of
astrocytic gap junctions (which blocks Ca21 waves) results in increased vulnerability of neurons to oxidativestress-induced disruption of Ca21 homeostasis and cell
death33. Induction of Ca21 waves in astrocytes results in
release of ATP, which appears to be crucial for propagation of the Ca21 waves34 and might also affect neurons
that possess ATP receptors.
Improved temporal and spatial resolution of intracellular Ca21 levels using confocal imaging approaches
has revealed events called Ca21 ‘sparks’, ‘blips’ and
‘puffs’ (Fig. 2c), which probably represent the elemental
processes underlying Ca21 waves and oscillations.
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M.P. Mattson et al. – Ca21 signaling in the ER
Although these processes were first characterized in frog
oocytes, they have been documented more recently in
neurons. Ca21 sparks and puffs occur spontaneously in
neurons and can also be induced by activation of either
IP Rs or RyRs (Ref. 35). Interestingly, such elementary
3
release sites occur where RyRs and IP3Rs are clustered,
and such sites are concentrated at neurite branch points,
which suggests these site have important roles in the
regulation of neurite outgrowth, signaling, or both.
Developmental and synaptic plasticity
21
Roles for ER-mediated Ca signaling in the regulation
of neurite outgrowth and synaptogenesis are likely, but
surprisingly underexplored. Studies of the expression
of genes encoding IP3Rs and RyRs during development
of the nervous system have established associations
between different isoforms of these channels and processes such as neurite outgrowth and synaptogenesis.
For example, IP31 is present in cortical neurons shortly
after their migration from the ventricular zone, and its
levels then increase markedly during the period of neurite outgrowth and synaptogenesis36. The ontogeny of
RyR synthesis in the brain is complex with the levels
of some isoforms changing dramatically between neuronal populations, and other isoforms being found at
almost constant levels from early embryonic development until adulthood37. Calcium has been established
as a key second messenger that is capable of mediating
responses of growth cones to environmental signals
such as neurotransmitters, neurotrophic factors and celladhesion molecules38–41. Several such signals are linked
to receptors that activate the Ins(1,4,5)P3 pathway, including muscarinic ACh receptors, metabotropic glutamate receptors and neurotrophin receptors. Direct
pharmacological manipulations of ER Ca21 homeostasis
have been shown to alter neurite outgrowth in various
systems. For example, dantrolene selectively suppresses
axon outgrowth in embryonic hippocampal neurons
(Fig. 2b), and depletion of ER Ca21 stores with thapsigargin inhibits neurite initiation and elongation in
cultured dorsal-root-ganglion neurons42.
Long-lasting changes in synaptic efficacy that result
from prior activity in neuronal circuits are believed to
have important roles in learning and memory. Both enhanced (LTP) and reduced (LTD) synaptic strength can
occur depending upon the stimulus parameters and
properties of the neuronal circuits being examined.
The ER has important roles in both presynaptic and
postsynaptic processes associated with synaptic transmission and plasticity. An example of a presynaptic
role for the ER comes from studies showing that blockade of ER Ca21 uptake enhances quantal release of
ACh from identified presynaptic terminals in Aplysia43.
Although it has been known for several decades that
increased intracellular Ca21 levels in synaptic terminals
(particularly in postsynaptic regions of dendrites) is
required for LTP and LTD, it has become apparent only
recently that Ca21 release from ER has a pivotal role in
these processes. Treatment of hippocampal slices with
agents that deplete ER Ca21 (thapsigargin and cyclopiazonic acid) blocks the induction of LTD (but not its
maintenance) without affecting basal synaptic transmission44. By selectively depleting ryanodine-sensitive
Ca21 stores and by microinjecting thapsigargin into (and
recording responses from) single postsynaptic cells, the
latter study has provided evidence that induction of LTD
requires Ca21 release from both a ryanodine-sensitive
TABLE 1. Physiological and pharmacological profile of endoplasmic reticulum
Ligand or drug
Main Target
Effect
Ins(1,4,5)P3
Adenophostin A
Acyclophostin
Xestospongin
Heparin
Caffeine
Ryanodine
Low concentration
High concentration
Dantrolene
FK-506, rapamycin
Thapsigargin
Tunicamycin, brefeldin A
2-deoxy-D-glucose
IP3 receptors
IP3 receptors
IP3 receptors
IP3 receptors
IP3 receptors
RyR
Channel opening, Ca21 release
Channel opening, Ca21 release
Partial agonist (pH dependent)
Block of Ca21 release
Block of Ca21 release
Channel opening, Ca21 release
RyR
RyR
RyR
FKBP
Ca21-ATPase
Protein-folding apparatus
Mitochondria
BCL2
Membrane
Channel opening, Ca21 release
Inhibition of Ca21 release
Block of Ca21 release
RyR channel stabilization
Block, Ca21 efflux, apoptosis
Inhibition of protein folding
Metabolic stress, GRP78
induction
Enhanced Ca21 uptake
Reduced oxidative stress
Abbreviations: FKBP, FK506 binding protein; GRP78, glucose regulated protein 78; RyR, ryanodine
receptor.
presynaptic pool and from Ins(1,4,5)P3-sensitive postsynaptic stores. Whole-cell voltage-clamp analyses of
cultured Purkinje cells, in which LTD was induced by
concommitent exposure to glutamate and electrical
depolarization, provides further evidence for a role for
ER Ca21 release in the induction of LTD (Ref. 45).
Using the technique of energy-dispersive X-ray microanalysis, Pozzo-Miller and colleagues46 provided evidence
that a subset of ER in dendrites of hippocampal neurons
in slice cultures serves as the major high-affinity Ca21
buffer after high-frequency stimulation. Recent studies
in which high resolution Ca21 imaging, and electrophysiological stimulation and recording methods were
applied to the parallel fiber–Purkinje-cell system have
revealed dynamic roles for Ins(1,4,5)P3-sensitive ER in
synaptic plasticity47–49. Repetitive stimulation of parallel
fibers resulted in Ca21 release that was restricted to
individual postsynaptic spines and adjacent dendritic
shafts. Studies in which caged Ins(1,4,5)P3 was released
locally in dendrites showed that the released Ca21
spreads only a few micrometers from the Ins(1,4,5)P3
release site, which indicates a mechanism for rapid
reuptake or buffering (or both) of the released Ca21
(Ref. 47). Released Ca21 induces a LTD that is limited
to synapses where the Ca21 level is increased. Recent
high-resolution confocal imaging of Ca21 in dendritic
spines of cultured hippocampal neurons has clearly
shown that release of Ca21 from ryanodine-sensitive
stores results in increased size of the spines and formation of new spines50, suggesting that Ca21 release
might elicit long-lasting changes in synaptic function
by changing the size and numbers of synapses.
The ER also has important roles in modulating gene
expression. For example, thapsigargin-induced Ca21 release in primary rat cortical neurons resulted in a large
increase in levels of mRNA encoding the ER chaperone
protein erp72 and heme oxygenase 1 (Ref. 51). Calcium
release from ER and ER stress can induce activation of
the transcription factors AP1 and NF-kB (Refs 52). AP1
has been linked to mechanisms of synaptic plasticity
in a variety of paradigms, including maintenance of
hippocampal LTP, although the gene targets of this
transcription factor that are crucial for changes in
synaptic efficacy have not been established53. NF-kB is
TINS Vol. 23, No. 5, 2000
225
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M.P. Mattson et al. – Ca21 signaling in the ER
a particularly intriguing transcription factor because it
exists in the cytosol in an inactive form and can be
activated locally in postsynaptic spines and dendrites
in response to synaptic activation54. Its activation is
associated with hippocampal synaptic plasticity, and
manipulations that block NF-kB activity can alter LTP
and LTD (Ref. 55).
Apoptosis, excitotoxicity and neurodegenerative
disorders
Apoptosis is a form of programmed cell death that
normally occurs during the development of the nervous system, and can also occur in various pathological settings including Alzheimer’s, Parkinson’s and
Huntington’s diseases, and stroke56–58. The biochemical
cascades that lead to apoptotic cell death are being elucidated and involve activation of one or more members of a family of cysteine proteases called caspases,
mitochondrial Ca21 uptake and membrane-permeability
transition, and release of factors from mitochondria
(for example cytochrome c) that ultimately induce nuclear DNA condensation and fragmentation. Alterations
of ER-mediated Ca21 homeostasis are sufficient to induce apoptosis. For example, thapsigargin can induce
apoptosis in many cell types including neurons, and
agents that suppress Ca21 release from ER (for example,
dantrolene) can protect neurons against apoptosis59.
While the ability of agents that perturb ER Ca21 homeostasis to induce neuronal apoptosis demonstrates that
proper functioning of this organelle is necessary for
neuronal survival, additional findings suggest that regulatory events occuring at the level of ER might control
the cell-death process. Bcl2 is an anti-apoptotic protein
that can prevent neuronal apoptosis in experimental
models of developmental cell death and neurodegenerative disorders. It associates with the ER and mitochondrial membranes and such associations might
stabilize Ca21 homeostasis60 and suppress oxidative
stress61. In addition, agents that disrupt ER-mediated
Ca21 regulation cause mitochondrial dysfunction and
caspase activation58,62.
Excitotoxicity is a mechanism of neuronal death that
involves overactivation of glutamate receptors, particularly under conditions of metabolic and oxidative stress,
resulting in cellular Ca21 overload; the ER contributes
to the excitotoxic process by releasing Ca21 (Ref. 63).
Accordingly, coactivation of Ins(1,4,5)P3-linked muscarinic ACh receptors in hippocampal neurons exacerbates glutamate toxicity64, whereas treatment of neurons
with agents that suppress ER-mediated Ca21 release protects against excitotoxicity65. Excitotoxic insults can also
result in neuronal apoptosis. For example, induction
of epileptiform discharges in entorhinal–hippocampal
slices by repeated tetanic stimulation results in apoptosis
of CA1 and CA3 neurons66; agents that block Ca21 release from ryanodine-sensitive stores can prevent such
excitotoxic apoptosis. In addition, studies of rodent
models of stroke have provided evidence for the involvement of ER Ca21 release in excitotoxic neuronal
apoptosis that occurs following cerebral ischemia67.
Abnormalities of ER-mediated Ca21 signaling have
recently been linked to the pathogenesis of Alzheimer’s
disease. Some cases of early-onset inherited Alzheimer’s
disease result from mutations in the gene encoding
presenilin 1 (Ref. 68). This protein is an integral membrane protein (probably with eight transmembrane
domains) that is located primarily in ER. The normal
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TINS Vol. 23, No. 5, 2000
function of this protein has not been established, but
targeted disruption of the gene encoding presenilin 1
in mice results in defects in somite formation and embryonic lethality; this phenotype is indistinguishable
from that of notch-1 knockout mice suggesting that
presenilin 1 functions in the notch signaling pathway.
Numerous Alzheimer’s-disease-linked mutations in presenilin 1 have been identified, each of which results in
a single amino-acid substitution; the mutations tend
to be located in two regions, one near transmembrane
domain 2 and the other in the cytoplasmic loop region.
Studies of cultured cell lines that overexpress mutated
presenilin-1 genes have documentated several adverse
effects of the mutations. One is the alteration of the
proteolytic processing of b-amyloid precursor protein,
which results in increased production of the neurotoxic
amyloid b-peptide (Ab1–42)69. Such altered proteolytic
processing might involve perturbations of ER function,
including protein trafficking. A second alteration observed is increased vulnerability of cells to apoptosis
induced by trophic factor withdrawal, exposure to Ab1–42
and other insults70,71. Increased vulnerability to apoptosis is associated with perturbed cellular Ca21 homeostasis and, specifically, enhanced Ca21 release from
Ins(1,4,5)P3- and ryanodine-sensitive stores71–73. Recent
studies of mutant presenilin-1 knock-in mice have
confirmed the adverse effects of presenilin 1 mutations
on neuronal Ca21 homeostasis, and have further shown
that the mutations render hippocampal neurons vulnerable to glutamate-induced Ca21 overload and excitotoxicity73. Perturbations of ER-regulated Ca21 homeostasis might also account for the recently reported
abnormalities in synaptic plasticity in transgenic mice
that possess mutant presenilin 1 (Refs 74,75).
The enhanced Ca21 release observed in neurons that
possess mutant presenilin 1 appears to result from an
alteration in ER responses to Ins(1,4,5)P3 and Ca21induced Ca21 release. Thus, studies of oocytes that
synthesize either wild-type or mutant presenilin 1 or
presenilin 2 show that Ca21 release induced by photolysis of caged Ins(1,4,5)P3 is greater in cells with mutant
presenilins (Refs. 76,77) and that Ca21 puffs are greatly
enhanced in oocytes that produce mutant presenilin 1
(Fig. 3a). Glutamate-induced Ca21 responses are increased in cultured hippocampal neurons with mutant
presenilin 1, and dantrolene treatment abolishes the
enhancement, suggesting that the adverse effect of presenilin-1 mutations on ER-mediated Ca21 regulation involves enhanced Ca21 release from ryanodine-sensitive
stores (Fig. 3). Co-immunoprecipitation data indicate
that presenilin 1 interacts with RyR or RyR-associated
proteins, or both, but direct interactions with IP3Rs have
not been found78. Another protein with which presenilins 1 and 2 interact is a Ca21-binding protein called
calsenilin; an interaction that alters proteolytic processing of the presenilins79. Most recently, it has been
reported that presenilin 2 interacts with the RyRassociated protein, sorcin80. The possible roles of calsenilin and sorcin in regulating ER-mediated Ca21 homeostasis in neurons, and their roles in the pathogenesis
of Alzheimer’s disease are unkown.
Additional alterations in ER function might contribute to neurodegenerative disorders, as suggested by
the following observations. The ER chaperone protein
GRP78 can suppress elevations of intracellular Ca21
levels following exposure of neurons to glutamate, and
this effect of GRP78 apparently results from reduced
REVIEW
M.P. Mattson et al. – Ca21 signaling in the ER
(b)
(c)
800
2.2
∆F/Fo
t
x
1.0
[Ca2+]i (nM)
∆F/Fo
wtPS1 M146V
PS1 mutant
600
Wild type
400
200
0
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0
50
100
t (s)
150
200
fEPSP slope (% change)
(a)
300
PSImut
WTPSI
NTg
250
200
150
100
0
–10
0
10
20 30
t (min)
40
50
60
trends in Neurosciences
Fig. 3. Presenilins: ER-resident proteins linked to the pathogenesis of Alzheimer’s disease. (a) Mutant presenilin 1 potentiates Ca21 ‘puffs’. Computer-enhanced line-scanning
confocal image illustrating the increased size of Ca21 puffs in oocytes containing mutant presenilin 1 (black wire frame) relative to wild-type presenilin 1 (solid, pseudocolor).
Color scale bar indicates relative levels of Ca21. (b) Calcium responses to glutamate are enhanced in hippocampal neurons containing mutant presenilin 1. Levels of Ca21
were measured prior to and after exposure to glutamate in cultured hippocampal neurons from wild-type and mutant presenilin 1 knock-in mice. Additional cultures from
mutant presenilin 1 knock-in mice were treated with 10 mM dantrolene (Dant) prior to exposure to glutamate. (c) LTP at hippocampal Schaffer-collateral–CA1 synapses
was enhanced in mutant presenilin 1 transgenic mice. Change in field EPSP slope after theta burst stimulation (arrow) in hippocampal slices from non-transgenic mice
(NTg), mice oversynthesizing wild-type presenilin 1 (WTPS1) and mice overproducing mutant presenilin 1 (PS1mut). Modified, with permission, from Ref. 75.
release of Ca21 from ryanodine-sensitive stores81. A
novel ER amyloid-binding protein (ERAB) was recently
described: its levels were found to be increased in
neurons in the brains of individuals with Alzheimer’s
disease, and it was suggested that binding of Ab to ERAB
might have an important role in the cytotoxicity of the
amyloid peptide82. Alterations in levels of enzymes in
the ER, such as a-glucosidase and fucosyl-transferase,
have been documented in studies of postmortem brain
tissue from individuals with Huntington’s and
Alzheimer’s diseases83, and experimental data suggest
that similar alterations can result in increased ER Ca21
release84. Studies of cellular Ca21 homeostasis in cells
containing mitochondria from platelets from individuals with Parkinson’s disease demonstrated a slower recovery from carbachol-induced elevation of cytoplasmic
Ca21 levels than did cells containing mitochondria from
control subjects85.
(particularly approaches that employ neuron-specific
promoters and conditional expression) and in cultured
neurons will advance our understanding of the essential
and modulatory functions of these proteins. Additional
goals of future research are to understand the signaling
mechanisms that regulate movement of ER within and
between neuronal compartments and how neuronal activity affects such movements; to elucidate the mechanisms by which ER integrates cellular Ca21 homeostasis with protein synthesis; to establish the molecular
mechanisms that govern interactions between ER, mitochondria and plasma membrane; and to understand
how ER dysfunction contributes to neurological disorders. Because many pathways that are essential for neuronal function, plasticity and survival are integrated with
Ca21 signaling mechanisms in the ER, a better understanding of the ER is of fundamental importance for a
wide spectrum of the neuroscience field.
Conclusions and future directions
Selected references
21
Mechanisms by which the ER controls neuronal Ca
homeostasis, and how this function of ER contributes
to neuronal plasticity and death, are being elucidated.
ER localization to dendrites, axons and their terminals
(growth cones and synapses) provides for local control
of Ca21 signals that effect changes in the structure and
function of neuronal circuits. Interactions of ER with
Ca21-regulating systems in the plasma membrane and
mitochondria provide for complex spatial and temporal
control of Ca21 levels that are central to regenerative Ca21
signaling mechanisms such as intra- and inter-cellular
‘waves’. Dysregulation of neuronal Ca21 homeostasis is
known to occur in many different disorders, including
stroke and Alzheimer’s disease, and emerging data from
studies of experimental models of such disorders indicate a central role for perturbed ER-mediated Ca21 regulation in the neurodegenerative process. Accordingly,
therapeutic approaches aimed at suppressing aberrant
ER-mediated Ca21 release (for example, treatment with
dantrolene) are proving effective in experimental models
and are poised for clinical trials.
The findings described herein suggest many exciting
directions for future research into the functions of ER in
neuronal plasticity and survival. Manipulations of genes
encoding Ca21-regulating proteins in the ER in mice
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BOOK
The Biology of Mind: Origins, Structures
of Mind, Brain and Consciousness
by M. Deric Bownds, Fitzgerald Science Press, 1999. $29.95 (xvi + 357 pages)
ISBN 1 891786 07 5
The venerable Psych. 101 is finding competition these days from introductions to
the biology of mind, which has created a
growing need for introductory cognitive
neuroscience texts. Bownds has helped fill
this need with his immensely readable book
The Biology of Mind. So engaging is this
book that I suspect it will find a secondary
audience with researchers interested in a
multi-disciplinary update of the brain and
cognitive sciences. Indeed, this is not your
standard introductory text. In contrast to
such works as Cognitive Neuroscience1, itself
an excellent but more advanced text,
Bownds is motivated more philosophically.
And, rather than summarize the state of the
art, he synthesizes contemporary research
into a specific model of the brain and cognition. Thus, instead of following the standard formula that begins with the signaling
properties of single cells, proceeds to early
sensory processing and then on to higher
cognitive function, Bownds frames his book
around a number of traditionally philosophical questions, which range from the subjective qualities of our experience and how
the human brain generates a ‘self’, to the
nature–nurture debate. Bownds raises these
philosophical issues because he believes we
are on the threshold of resolving them
with a biological approach, although their
sometimes brief discussion in later chapters
raises the question of how much real progress has been made regarding these difficult
issues, a point I take up below. Although
some might find this too speculative a
starting point, and it is debatable whether
these really are the questions that motivate
the majority of cognitive neuroscientists,
it nevertheless provides an engaging entry
point for students and also helps to motivate
the later descent into the biochemistry of
the cell and neural systems.
The Biology of Mind differs from standard
texts in another way. Whereas many cognitive neuroscience texts discuss evolution
only in passing, Bownds makes it an organizing theme. In particular, he believes that
an evolutionary perspective supports a
‘society of mind’ view, one that likens the
human brain to a Swiss Army knife. This view
suggests that the human brain is a hodge–
podge of evolutionary adaptations, a confederation of specialized modules that reflect the evolutionary pressures of our
ancestral environment. This evolutionary
perspective figures prominently in the
book’s central chapters, which are in Part III,
‘The Society of Mind’. There, a chapter is
devoted to each of the biological bases of
visual perception, motor control, emotion
and language, all viewed as a collection of
evolved modules. The purpose of Part I,
‘Evolving Mind’, is to show how biological
evolution has shaped the minds we use
today. Bownds does so by way of a rousing
exploration of the themes of neural evolution and an overview of neural systems,
stopping along the way to consider results
in cognitive ethology and the transition from
early hominids to modern humans.
Whether this evolutionary perspective
adds significantly to our understanding of
neural systems and cognitive function is a
matter of debate. The editors of a recent
issue of Current Opinions in Neurobiology2 on
Acknowledgments
The authors’
research is supported by the
National Institute
on Aging and the
Alzheimer’s
Association
(M.P.M.), the
Medical Research
Council of Canada
(J.D.G. and P.N.S.),
and the Alzheimer’s
Society of Canada
(J.D.G.).
REVIEWS
the evolution of the nervous system, for
example, excluded purposefully such topics
as the evolution of language and complex
social behaviors, citing the lack of progress
and consensus in these areas. Although the
editors’ rather circumspect view might err
too strongly on the side of caution, evolutionary accounts are extremely controversial and it remains questionable whether the
evolved module account sheds much light
on our understanding of nervous-system
function and organization. This is further
complicated by the fact that some of the
authors Bownds cites who are in support of
the evolved module view, such as Terrence
Deacon, do not share Bownds enthusiasm
for the modular story.
Bownds himself appears not to notice
the tension between the evolved module
view, and the account of neural development and the cellular basis of learning that
he presents in chapter 6, one of the best
chapters in the book. The emphasis is on
developmental plasticity, which echoes an
afferent specification view of brain development, by which cortical areas become
functionally specialized under the influence
of thalamic activity. Yet, it is not at all clear
whether this view of development is consistent with the evolved mental module
view. In downplaying the extent of developmental plasticity, evolutionary psychologists, for example, highlight early instinctive
behaviors and conclude that the brain is
highly structured prior to experience.
Indeed, I was surprised that there was no
reference to Steven Mithen’s Prehistory of
Mind3, as Mithen argues that the essential
difference between early hominids and
modern humans is our protracted development, which results in cognitive fluidity
rather than modularity. In other places,
Bownds enthusiasm for a modular brain
leads him to overstate the strength of some
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