Refinement of the retinogeniculate pathway
William Guido
J. Physiol. 2008;586;4357-4362; originally published online Jun 12, 2008;
DOI: 10.1113/jphysiol.2008.157115
This information is current as of September 28, 2008
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J Physiol 586.18 (2008) pp 4357–4362
SYMPOSIUM REPORT
Refinement of the retinogeniculate pathway
William Guido
Virginia Commonwealth University Medical Center, Department of Anatomy and Neurobiology, Richmond, VA 23298, USA
Much of our present understanding about the mechanisms contributing to the activitydependent refinement of sensory connections comes from experiments done in the
retinogeniculate pathway. In recent years the mouse has emerged as a model system of study.
This review outlines the major changes in connectivity that occur in this species and a potential
mechanism that can account for such remodelling. During early postnatal life when spontaneous
activity of retinal ganglion cells sweeps across the retina in waves, retinal projections from the two
eyes to the dorsal lateral geniculate nucleus (LGN) segregate to form non-overlapping eye-specific
domains. There is a loss of binocular innervation, a pruning of excitatory inputs from a dozen or
more to one or two, and the emergence of inhibitory circuitry. Many of these changes underlie
the development of precise eye-specific visual maps and receptive field structure of LGN neurons.
Retinal activity plays a major role both in the induction and maintenance of this refinement.
The activity-dependent influx of Ca2+ through L-type channels and associated activation of
CREB signalling may underlie the pruning and stabilization of developing retinogeniculate
connections.
(Received 19 May 2008; accepted after revision 9 June 2008; first published online 12 June 2008)
Corresponding author W. Guido: Department of Anatomy and Neurobiology, VCU Medical Center, Sanger Hall,
1101 E. Marshall Street, Richmond, VA 23298, USA. Email: [email protected]
The retinogeniculate pathway of the mouse undergoes
extensive remodelling during early postnatal life (see
Fig. 1; Torborg & Feller, 2005; Huberman, 2007) and with
the advent of transgenic models this system has become
a major experimental platform to study the mechanisms
underlying the activity-dependent refinement of sensory
connections. Thus, information about when and by what
means retinal axons establish and then rearrange their
patterns of connectivity in the lateral geniculate nucleus
(LGN) is needed. Here I provide a brief review of my lab’s
work as well as others that pertain to the development
and remodelling of retinogeniculate connections. Topics
to be discussed include the development of eye-specific
segregation in the LGN, the structural and functional
remodelling of retinogeniculate connections, the role of
retinal activity in shaping and maintaining patterns of
connectivity, and the potential mechanisms underlying
the remodelling of these connections.
This report was presented at The Journal of Physiology Symposium on
Retinal ganglion cells in model organisms: development, function and
disease, which took place in Fort Lauderdale, FL, USA, 26 April 2008. It
was commissioned by the Editorial Board and reflects the views of the
authors.
C 2008 The Author. Journal compilation C 2008 The Physiological Society
The development of eye-specific segregation
in the lateral geniculate nucleus
A cardinal feature of the mammalian retinogeinculate
pathway is the segregation of retinal inputs from the
two eyes (Fig. 1B). In the mouse there is no obvious
lamination pattern that partitions projections by eye.
Instead, projections from each eye are organized into
non-overlapping territories called eye-specific domains
that can only be visualized by the anterograde labelling
of retinal ganglion cells. When cholera toxin β subunit
conjugated to different Alexa fluorescent dyes are injected
into one eye or the other, estimates of the spatial extent for
projections arising from each eye as well as the degree
of overlap that exists between them can be obtained
(Muir-Robinson et al. 2002; Jaubert-Miazza et al. 2005).
In adults, axons from nasal and most of temporal
retina cross at the optic chiasm and project to the LGN,
occupying as much as much as 85–90% of its total area.
A much smaller group of retinal ganglion cells (5%) from
the ventro-temporal region have axons that do not cross
at the optic chiasm, but instead project ipsilaterally to
terminate in the antero-medial region of LGN. Uncrossed
projections form an irregularly shaped cylinder that runs
rostral to caudal through LGN, occupying about 10–12%
of the total area, but sharing little (< 1–2%) if any territory
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W. Guido
with crossed projections. While a coarse visuoptopic map
is established shortly after retinal axons innervate the
LGN, eye-specific patterning is not apparent at birth
but emerges just after the first postnatal week. Initially,
J Physiol 586.18
crossed and uncrossed axons innervate the LGN at slightly
different times, with crossed projections arriving earlier
(E15–16) than uncrossed ones (P0–2) (Godement et al.
1984; W. Guido unpublished observations). At these
Figure 1. Summary of retinogeniculate refinement
The major events and changes that occur along the retinogeniculate pathway during the first few weeks of
postnatal life are shown. In A, spontaneous and visually evoked retinal activity, are displayed as poststimulus time
histograms. The shaded region represents the response to a visual stimulus. In B, D and E, red and green represent
retinal inputs arising from the contralateral and ipsilateral eye, respectively. In B, yellow depicts regions of overlap.
In C and D, LGN neurons labelled I and R depict interneurons and relay cells, respectively. In D, weak and strong
retinal inputs are displayed as opened and filled symbols, respectively.
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J Physiol 586.18
Refinement of the retinogeniculate pathway
ages, crossed projections span almost the entire LGN. As
uncrossed axons innervate the LGN, they too are diffusely
organized but by P2 they begin to establish a rudimentary
patch of terminal arbors in the dorso-medial sector.
Between P2 and P5 the inputs from the two eyes share a
substantial amount of terminal space in LGN. Our
estimates of spatial extent reveal that at P3 uncrossed
projections occupy about 60% of the LGN and overlap
with crossed ones by as much as 57%. Between P3 and P7
there is a rapid retraction of uncrossed terminal arbors.
Nonetheless, even at P7 uncrossed projections still occupy
about 25% of LGN and share close to 20% with crossed
projections. By P10, retinal projections from the two eyes
show clear signs of segregation, and by natural eye opening
(P14), they are well segregated and resemble the pattern
found in the adult.
Patterns of synaptic connectivity
in the developing LGN
The anatomical segregation of retinal projections
into eye-specific domains is accompanied by major
modifications in the pattern of synaptic connectivity
(Fig. 1D). In vitro intracellular recordings of the synaptic
responses of LGN cells illustrate the presence of functional
retinogeniculate connections at very early postnatal ages
(Mooney et al. 1996; Chen & Regehr, 2000; Jaubert-Miazza
et al. 2005). Using an explant preparation that that
preserves large segments of each optic nerve, we have
shown that many developing LGN cells receive direct
binocular excitatory input (Jaubert-Miazza et al. 2005;
Ziburkus & Guido, 2006). Additionally, estimates of
retinal convergence indicate that a single LGN cell can
receive weak synaptic input from as many as one to
two dozen retinal ganglion cells (Chen & Regehr, 2000;
Jaubert-Miazza et al. 2005). After the first postnatal week,
as retinal projections recede and clear signs of eye-specific
segregation emerge, the degree of retinal convergence
begins to diminish. By the second postnatal week, LGN
cells receive far fewer retinal inputs that arise either
from one eye or the other. During the following weeks,
additional pruning occurs so that eventually LGN cells
receive strong monocular input from as few as 1–3 retinal
ganglion cells. We have begun to examine where and
how retinal inputs are distributed on LGN relay cells
by combining our anterograde labelling of retinal axons
with 3-D confocal reconstructions of relay cells filled with
biocytin (Fig. 1E). Preliminary findings have shown that
at early ages (P7–9) retinal contacts can occupy as much as
50% of the surface area of relay cells. Retinal contacts are
widespread and located on somata as well as proximal and
distal regions of dendrites. We have also found that retinal
contacts arise from both eyes, but the bulk is dominated by
just one eye. This seems to be consistent with our electro-
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physiological experiments showing that while cells receive
multiple retinal inputs from both eyes, the inputs from one
outweigh those of the other (Ziburkus & Guido, 2006).
There is also progressive elimination of contacts with age
so that by the third postnatal week they arise from one
eye and occupy only 1–5% of the total surface area of
LGN cells. While the dendritic fields of relay cells show
moderate expansion, to our surprise, we find that many
aspects of dendritic complexity (e.g. number of primary
dendrites, branch order, and number of branch points)
remain relatively constant between postnatal weeks 1 and
3 (Fig. 1E). Taken together, these data suggest that the
developmental plan of relay cells is established quite early
and the dendritic scaffold for synaptic remodelling is in
place by the first postnatal week.
During this pruning process, there are corresponding
changes in synaptic strength and in the receptor
composition of excitatory glutamate-mediated responses
(Fig. 1C–D; Chen & Regehr 2000; Liu & Chen, 2008).
Initially, excitatory postsynaptic currents are relatively
small (weak) and mediated almost exclusively by NMDA
receptor activation. As pruning proceeds and the
remaining excitatory responses increase in amplitude
(strength), AMPA-mediated responses emerge. At a time
when cells receive just a few retinal inputs, there is a 50-fold
increase in synaptic strength and a 4-fold increase in the
AMPA to NMDA receptor current ratio.
In addition to the remodelling of excitatory
connections, inhibitory circuits that involve GABAeric
interneurons of the LGN appear (Fig. 1C–D). In the
adult, retinal axons possess collateral branches that
make excitatory connections with intrinsic interneurons,
which in turn form feedforward inhibitory connections
with relay cells. Our anatomical and electrophysiological
experiments suggest that inhibitory responses in LGN
relay cells are not fully developed at early postnatal
ages (Ziburkus et al. 2003; Jaubert-Miazza et al. 2005;
Slusarczyk et al. 2006). They start to appear around postnatal day 5–7 but do not fully mature until near the
time of natural eye opening (P14). While the balance of
excitatory and inhibitory responses seem to develop at
different times, the functional significance of this sequence
remains unexplored. Perhaps the delayed maturation
of inhibitory circuitry allows for an increased level of
membrane depolarization which is needed to activate
events implicated in synaptic remodelling (see below).
Retinal activity mediates the induction
and maintenance retinogeniculate refinement
The refinement of connections in LGN has been attributed
to the coordinated firing patterns of spontaneous
retinal activity (Torborg & Feller, 2005). Even before
photoreceptors are equipped to activate bipolar cells,
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W. Guido
neighbouring retinal ganglion cells fire spontaneously in
rhythmic bursts that spread across the retina in a wave-like
fashion (Fig. 1A; Wong, 1999; Demas et al. 2003). When
these retinal waves are disrupted or completely eliminated,
retinal axon arbors in LGN remain diffuse and fail to
segregate properly into eye-specific domains (Torborg &
Feller, 2005). Most notable are the observations made
in two transgenic mice lines. Animals missing the β2
subunit of nicotinic acetylcholine (nACh) receptor lack
an early phase of retinal wave activity, one that is mediated
largely by cholinergic synaptic transmission (Bansal et al.
2000). As a result, retinal projections remain diffuse
through early postnatal life and fail to segregate properly
into eye-specific domains (Muir-Robinson et al. 2002).
In the no-b wave (nob1) mouse, a mutant that lacks
nyctalopin, a protein essential for photoreceptor and
ON-bipolar cell synaptic transmission (Gregg et al. 2003),
abnormally frequent and persistent retinal waves occur at
the time when axon segregation is complete and retinal
waves are normally replaced by visually evoked activity
(Demas et al. 2006). These persistent high frequency waves
cause newly established eye-specific domains in LGN to
de-segregate and return to a diffuse state. In addition to
the abnormal retinal wave activity, these mice exhibit a
severe loss of visual sensitivity, lacking an ERG b-wave and
discernable on- or off-stimulus evoked visual responses
(Gregg et al. 2003, 2007). These combined deficits
raise the possibility that the persistence of abnormal
spontaneous retinal activity, perhaps at the expense of
visually driven activity, disrupts retinogeniculate axon
segregation. Studies employing a delayed dark rearing
protocol further suggest that the strength and final patterns
of connectivity in LGN requires patterned visually evoked
activity (Hooks & Chen, 2006; Hooks & Chen, 2008).
Taken together, these studies suggest that some aspect
of spontaneous retinal waves and/or visually evoked
activity is important for the continued maintenance of
newly established connections. Thus, activity-dependent
refinement in LGN comprises two somewhat overlapping
phases (Fig. 1, bottom panel): an initial inductive phase
where eye-specific domains are established and the bulk
of synaptic pruning takes place, and a maintenance phase
where newly refined connections require some form of
retinal activity in order for them to stabilize, increase in
strength, and eventually consolidate to form an adult-like
pattern of connectivity.
While there is some debate about whether retinal
waves play an instructional role in retinogeniculate
axon segregation (Chalupa, 2007), the nearest-neighbour,
same-eye relations underlying the spatiotemporal
patterning of waves make them a prime candidate
for promoting Hebbian synaptic plasticity. In Hebbian
models, temporally correlated activity between pre- and
postsynaptic elements leads to a strengthening and
consolidation of synapses, whereas asynchronous activity
J Physiol 586.18
or the absence of activity results in synapse weakening and
elimination. Hebbian-based changes in synaptic strength
have been noted in several developing vertebrate sensory
structures and linked to intracellular signalling cascades
that promote the structural refinement of connections.
Long-term modifications in synaptic strength may also
embody the synaptic rearrangements occurring in LGN.
Bidirectional changes in synaptic strength have been
reported at the retinogeniculate synapse (Butts et al. 2007).
These modifications seem to adhere to a Hebbian learning
rule in which the relative timing between presynaptic
high frequency stimulation (HFS) of retinal fibres (similar
to waves) and postsynaptic depolarization (via current
injection) of an LGN cell proves to be the defining feature.
Cells exhibit LTP when optic tract stimulation and LGN
depolarization are coincident or overlap, but show mild
LTD when pairing is non-overlapping. Using a rodent
explant preparation that preserves retinal connections
from the two eyes, we also show that that HFS of
retinal afferents leads to changes in synaptic strength
(Guido, 2006; Ziburkus et al. submitted). The polarity
and magnitude of these changes are both age and
pathway specific. In one set of intriguing experiments
involving binocularly innervated LGN cells, heightened
activity along the tetanized pathway leads to an increase
in synaptic strength (homosynaptic LTP) as well as a
reduction in synaptic strength (heterosynaptic LTD) along
the untetanized, less active pathway.
The role of L-type Ca2+ channels in the developmental
remodelling of retinogeniculate connections
A critical issue to resolve is the identification of neural
elements and signalling events that mediate changes
in retinogeniculate connectivity. A likely candidate
involves the activity-dependent influx of Ca2+ associated
with NMDA receptors and/or voltage-dependent Ca2+
channels. While the role of NMDA receptors figures
prominently in many models of activity-dependent
refinement, their involvement at the retinogeniculate
synapse seems far less important. Correlated firing
between retinal ganglion cells and LGN cells persist in
the absence of NMDA receptors (Mooney et al. 1996) and
NMDA receptor blockade does not seem to interfere with
eye-specific segregation, at least in the ferret (Smetters
et al. 1994). Instead, NMDA receptors in immature LGN
cells seem to promote sustained levels of membrane
depolarization that lead to spike firing (Liu & Chen, 2008),
perhaps to ensure that retinal wave activity is relayed to
the developing visual cortex (Hanganu et al. 2006) and
utilized for the refinement of topographic maps (Cang
et al. 2005). Their voltage dependency and long decay times
also contribute to the spatial and temporal summation of
EPSPs and the activation of voltage gated L-type Ca2+
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J Physiol 586.18
Refinement of the retinogeniculate pathway
channels (Lo et al. 2002), an element that may represent
a more likely substrate for activity-dependent plasticity in
LGN.
In LGN, L-type channels are located primarily on
somata and proximal dendrites (Budde et al. 1998;
Jaubert-Miazza et al. 2005). These channels seem to
reside close to retinal synapses (Rafols & Valverde, 1973;
Slusarczyk et al. 2006), thus allowing for coordinated
coactivation and amplification of retinally evoked
postsynaptic events (Fig. 1C). In fact, strong and/or
repetitive stimulation of retinal fibres evokes EPSPs
that activate high-amplitude, long-lasting, slow-decaying
depolarizations (Lo et al. 2002; Jaubert-Miazza et al.
2005; Liu & Chen, 2008). These so-called plateau
potentials have a voltage dependency and pharmacology
that resembles the activation of high-threshold L-type
(long-lasting) Ca2+ channels (Kammermeier & Jones,
1997). Synaptically evoked plateau potentials in LGN are
transient events. They are encountered far more frequently
at early postnatal ages but then decline with age, so
that after natural eye opening they are rarely observed
(Jaubert-Miazza et al. 2005). A number of factors seem
to contribute to this, including the density of L-type
expression, emergence of inhibitory synaptic activity, and
the maturation of intrinsic membrane properties. Perhaps,
the most important factors seem to be the high degree
of retinal convergence and heightened NMDA activity
noted in immature LGN cells (Lo et al. 2002; Liu &
Chen, 2008). These events lead to sustained levels of
depolarization and thereby greatly increase the likelihood
that high-threshold L-type channels are activated. In
vivo, the driving force behind such activation appears
to be retinal waves (Mooney et al. 1996). The episodic
barrages of retinally evoked EPSPs brought about by
retinal waves are of sufficient amplitude and duration
to activate plateau potentials. In vitro recordings of
synaptic responses reveal that repetitive stimulation of
retinal afferents in a manner that approximates the
high frequency discharge of retinal waves gives rise to
robust plateau activity (Lo et al. 2002; Jaubert-Miazza
et al. 2005; Butts et al. 2007). The Ca2+ influx through
L-type channels has been linked to the activation of
transcription factors that lead to the expression of genes
associated with synaptic plasticity and remodelling (Lonze
& Ginty, 2002). A likely candidate involves the cAMP
response element (CRE/CREB) transcription pathway
(Mermelstein et al. 2000; Dolmetsch et al. 2001). The CRE
binding protein (CREB) is a Ca2+ and cAMP regulated
transcriptional activating protein shown to be important
for retinogeniculate axon segregation. In the mouse LGN,
CRE-mediated gene expression peaks during early postnatal life (Pham et al. 2001) and mutant mice that show
reduced levels of L-type Ca2+ channel activity or decreased
levels of CRE fail to segregate properly (Cork et al. 2001;
Pham et al. 2001). Thus, the Ca2+ influx through L-type
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channels may provide the basis for the pruning and
stabilization of developing retinogeniculate connections.
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Acknowledgements
This work was supported by EY12716. For their invaluable
scientific contributions, I would like to thank past (Jokubas
Ziburkus, Fu-Sun Lo, Erick Green, Lisa Jaubert-Miazza, Kim
Bui, Jeremy Mills) and present (Thomas Krahe, Rana El-Danaf,
Emily Dilger, Tania Seabrook) lab members, as well as the labs
of Martha Bickford, Ron Gregg and Rachel Wong.
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Refinement of the retinogeniculate pathway
William Guido
J. Physiol. 2008;586;4357-4362; originally published online Jun 12, 2008;
DOI: 10.1113/jphysiol.2008.157115
This information is current as of September 28, 2008
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