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100
The Molecular and Structural Basis
of Amblyopia
Jason E. Coleman, Arnold J. Heynen, and Mark F. Bear
Amblyopia is a common cause of vision loss during
infancy and childhood (Holmes & Clarke, 2006). Visual
dysfunction in amblyopia stems from conditions that
degrade image formation or eye alignment prior to
adolescence; these include strabismus, uncorrected
refractive errors (e.g., anisometropia), and cataracts
(Doshi & Rodriguez, 2007). The abnormal development of synaptic connections in the primary visual
cortex (V1) is responsible for the loss of vision.
The substrate for binocular vision in mammals is the
convergence of visuotopically matched inputs onto
common postsynaptic targets in V1. Early in development, the wiring of visual connections from dorsal
lateral geniculate nucleus (LGN) to V1 is largely guided
by a genetic program and intrinsic neural activity (Crair
et al., 2001; Crowley & Katz, 2000; LeVay, Stryker, &
Shatz, 1978). Beyond this period, the refinement and
maintenance of synaptic connections for encoding
behaviorally relevant information depends upon the
quality of visual experience from the outside world. In
amblyopia, the disruption of normal binocular visual
experience leads to the weakening and reorganization
of visual circuitry in V1.
The pioneering work of David Hubel and Torsten
Wiesel, who received the 1981 Nobel Prize in Physiology
or Medicine for their studies on visual cortical function
and plasticity, has served as the platform for modern
mechanistic studies of amblyopia. They found that a
prolonged period of monocular lid suture begun shortly
after birth caused a shift in the ocular dominance (OD)
of cortical neurons so that the majority failed to respond
to stimulation of the deprived eye (Hubel & Wiesel,
1964). Using this monocular deprivation (MD) paradigm, they also discovered anatomical correlates of
visual impairment (Wiesel & Hubel, 1963b). The most
robust correlate of the OD shift was the demonstration
that in binocular cortex the territory innervated by
open-eye thalamocortical afferents in layer 4 expands
after MD whereas the territory innervated by deprivedeye afferents shrinks (LeVay, Wiesel, & Hubel, 1980).
Together, these studies provided the first descriptions
of what is now known as OD plasticity, and this paradigm has proven to be invaluable for studying mechanisms underlying experience-dependent plasticity in
cortex and amblyopia.
In this chapter, we provide an overview of work that
has led to a greater understanding of the molecular and
structural mechanisms of amblyopia.
Investigating the Mechanisms of
Amblyopia in the Mouse
As research efforts have increasingly focused on elucidating the molecular and cellular bases of amblyopia,
the mouse visual system (see figure 100.1A) has become
the model of choice. The fine organization of primary
visual input to V1 (i.e., thalamocortical axons) differs
between rodents and carnivores or primates, but the
basic circuitry underlying vision and the transmission
of visual information from retina to thalamus to V1 is
conserved. It is important at this point to draw a distinction between OD plasticity and OD column plasticity.
OD columns reflect the segregation of LGN afferents
in layer 4 of visual cortex and are arranged as regularly
spaced bands or stripes. Present in some carnivores
(e.g., cat and ferret) and some primates (e.g., macaque
and human), they provide a convenient pattern for
visualizing eye-specific thalamocortical input, which can
be illuminated by injecting a transsynaptic tracer into
one eye (Hubel & Wiesel, 1968). However, they are not
a consistent feature of binocular visual cortex and are
not a predictor of the capacity for OD plasticity, even
among primates (Horton & Adams, 2005). OD plasticity can be measured physiologically by recording from
single neurons or populations of neurons that receive
input from both eyes, or anatomically by monitoring
synaptic and axonal structures, without regard to
whether they are in eye-specific columns (Hubel &
Wiesel, 1968) or innervate cortex in a salt-and-pepper
arrangement (Mrsic-Flogel et al., 2007).
In addition to the fact that mice are inbred and can
be genetically manipulated, mouse visual cortex
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Figure 100.1 Binocular vision and ocular dominance (OD) plasticity in the mouse. (A) The representation of visual space
in the cortex and the site in cortex where OD plasticity is monitored. The left and middle panels show how information for
one visual hemifield viewed by the ipsilateral eye (blue region, monocular visual field) and by both eyes (green region, binocular visual field) is represented in V1. The eye ipsilateral to the hemifield (blue) projects to the contralateral hemisphere
whereas the contralateral eye viewing the same space (yellow) projects to the ipsilateral hemisphere (numbers indicate visual
degrees; globe not drawn to scale). The right panel shows a schematic of the mouse visual pathway (V1B, binocular segment;
V1M, monocular segment; dLGN, dorsal lateral geniculate nucleus). Binocular responses (and structures) are recorded (and
imaged) in V1B contralateral to the deprived eye. (B) Physiological measurements of plasticity at thalamocortical synapses (e.g.,
layer 4 visually evoked potentials) of the mouse reveal two sequential changes—deprived-eye depression after 3 days of monocular deprivation (MD) and open-eye potentiation after 7 days of MD (blue = contralateral, deprived eye; yellow = ipsilateral,
open eye). (C) Proposed model for how molecular and structural changes coincide with and contribute to pathway-specific
functional plasticity in V1B (e.g., deprived-eye depression and thalamocortical axon retraction). The graph highlights two key
points: (1) The functional consequences of short-term and long-term MD are the same, and (2) the kinetics (i.e., rapid or slow
as indicated by arrows) of structural plasticity relative to functional plasticity have yet to be fully elucidated.
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possesses several characteristics that have made it advantageous as a model for studying OD plasticity. First,
cortical processing of binocularity begins with the convergence of thalamic inputs onto layer 4 neurons in V1
rather than with the convergence of layer 4 inputs onto
layer 2/3 neurons in V1 that occurs in primates, a
pattern of connectivity that potentially simplifies the
analyses of the synaptic changes that accompany OD
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plasticity. Second, the absence of a columnar organization makes feasible the use of chronic field potential
recordings from awake animals since cells with varying
degrees of eye dominance are intermingled in the binocular segment of V1 (Mrsic-Flogel et al., 2007). Third,
the fact that the mouse visual cortex is relatively undifferentiated (e.g., compared to monkey V1) suggests
that insights gained here might apply broadly across
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species and cortical areas (Coleman, Law, & Bear,
2009).
Using chronic visually evoked potential recordings in
layer 4 of mouse V1, Frenkel and Bear (2004) showed
that the OD shift toward the nondeprived eye occurs by
two distinct phases: a weakening of deprived-eye
responses after 3 days of MD and a strengthening of
open-eye responses after 7 days of MD (see figure
100.1B). This sequence of rapid deprived-eye depression and delayed open-eye potentiation has also been
noted using other measures of plasticity (Hofer et al.,
2006; Kaneko et al., 2008; Mrsic-Flogel et al., 2007) and
in other species (Mioche & Singer, 1989) and reflects
functionally meaningful changes in sensory processing.
In rats, a dramatic reduction in visual acuity assessed
through visually guided behavior occurs through the
deprived eye following MD (Iny et al., 2006; Prusky,
West, & Douglas, 2000). In the same visually guided
task, open-eye performance was enhanced following
MD (Iny et al., 2006).
Homosynaptic Long-Term Depression and
Ocular Dominance Plasticity
An important question when considering the mechanism of deprived-eye depression is whether it is simply
a consequence of the absence of activity in the deprived
eye or whether it is triggered by activity in the deprived
eye that no longer correlates with a strong cortical
response. The question is critical because it cleanly
divides potential mechanisms. In the former model,
deprived-eye depression is simply explained by disuse,
the silencing of afferent synapses. In the latter model,
the plasticity is triggered instead by the untimely release
of neurotransmitter by afferent synapses. A number of
lines of evidence suggest that the deprivation effects are
triggered by activity rather than inactivity. For example,
the depression of input from one eye after strabismus
cannot be explained by disuse but is readily explained
by a loss of pre- and postsynaptic correlations. Moreover, simple blurring of images on the retina with an
overcorrecting contact lens is as effective as monocular
lid closure in inducing an OD shift (Rittenhouse et al.,
2006). Finally, intraocular injection of tetrodotoxin,
which silences all output from the retina, fails to induce
robust deprived-eye depression in the cortex (Frenkel
& Bear, 2004; Rittenhouse et al., 1999). Together, the
data suggest that synaptic depression in cortex is driven
to occur by poorly correlated afferent activity. Because
deprived-eye synapses apparently trigger their own
demise via untimely release of neurotransmitter, the
mechanisms responsible are said to be “homosynaptic”
(Smith, Heynen, & Bear, 2009).
To study the mechanisms of homosynaptic depression, a paradigm was introduced by Dudek and Bear
(1992) in which tetanic electrical stimulation of synapses was used to induce long-term depression (LTD)
of synaptic transmission in brain slices (reviewed by
Bear, 2003). Although it is now appreciated that there
are many mechanisms for LTD in different brain
regions, some of these are well conserved (Malenka &
Bear, 2004). The study of LTD in hippocampus and
visual cortex has led to a detailed understanding of how
activity triggers a loss of synaptic strength.
Intracortical circuitry is complex, and it is reasonable to question where the primary site of plasticity is.
Although the work of Hubel and Wiesel clearly implicated plasticity of geniculocortical synapses, this could
be a consequence rather than a primary cause of
deprived-eye depression. Recent studies in mouse
have indicated, however, that depression of thalamocortical synaptic transmission after MD is very rapid,
occurring at the same rate as the OD shift (Khibnik,
Cho, & Bear, 2010). Thus, although modifications of
other synapses clearly occur after MD, the changes in
thalamocortical synaptic transmission alone are sufficient to account for the OD shift. These findings
justify a focus on plasticity of excitatory synaptic transmission as the primary cause of deprived-eye depression. As mentioned, LTD of excitatory synaptic
transmission has been studied in slices of visual cortex
to gain insight into the mechanisms of the OD shift.
To assess the relevance of LTD to naturally occurring
plasticity, two approaches have been taken: (1) tests of
the hypothesis that LTD is induced in visual cortex by
MD and (2) investigation of shared requirements for
induction or expression of LTD and deprived-eye
depression. Although the contribution of LTD mechanisms to OD plasticity was once considered to be controversial, it is now clear that these same molecular
mechanisms are engaged by MD and necessary for the
loss of visual responses. Some of this evidence is summarized below.
LTD Is Induced by MD and Necessary for the Loss
of Visual Responsiveness
The “canonical” LTD mechanism in the CA1 region of
hippocampus was used to guide early mechanistic
studies in the visual cortex. In CA1, weak activation of
N-methyl-D-aspartate (NMDA) receptors and a rise in
postsynaptic Ca2+ activate a postsynaptic protein phosphatase cascade that alters the phosphorylation state of
AMPA receptors, which are subsequently internalized
by clathrin-dependent endocytosis (Malenka & Bear,
2004). These changes can be detected biochemically
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using phosphorylation site-specific antibodies and
assays of receptor surface expression. The biochemical
signature of LTD has been used as a “molecular fingerprint” to test whether similar changes occur in visual
cortex following a period of MD. This has been directly
examined in both rat and mouse visual cortex. The
results support the hypothesis that MD sets in motion
changes that are identical to LTD in visual cortex
(Heynen et al., 2003; McCurry et al., 2010).
To find out if LTD and deprived-eye depression
utilize the same molecular cascades, one can ask
whether LTD in slices is occluded by prior MD. Indeed,
brief periods of MD (i.e., the minimum time required
to cause maximal deprived-eye depression) cause a significant reduction in the amount of LTD elicited in rat
(Heynen et al., 2003) and mouse visual cortical slices
(Crozier et al., 2007). Mimicry and occlusion are two
criteria that must be satisfied to conclude that two
methods to induce synaptic depression converge on
common mechanisms. By these criteria, both MD and
LTD engage the same molecular mechanisms.
Although the evidence summarized above indicates
that MD induces LTD, these studies do not reveal the
relative contribution of LTD mechanisms to the OD
shift after MD. There are two ways one can address this
question of whether LTD mechanisms are necessary for
deprived-eye depression after MD: (1) Determine
whether both processes are affected by the same
modulators and (2) determine whether both processes
depend on the same mediators. The distinction between
modulators and mediators is important. Modulators are
factors that may alter the induction requirements under
specific experimental conditions. Mediators are the
molecular events that directly couple synaptic activity to
the change in synaptic strength (Malenka & Bear,
2004).
An example of a common modulator is the state of
inhibition. Because LTD induction requires an appropriate level of voltage-dependent NMDA receptor activation, the stimulation requirements for LTD will vary
depending on the status of postsynaptic excitability
(Steele & Mauk, 1999). Excitability is finely controlled
by GABAergic inhibition. The reduction in visual cortical inhibition caused by genetic deletion of glutamic
acid decarboxylase 67 both impairs the ocular dominance shift (Hensch et al., 1998) and prevents LTD
with standard stimulation protocols (Choi et al.,
2002). Although this correlation supports the general
notion that OD plasticity and LTD have similar
requirements, shared modulation is not particularly
strong evidence because it is to be expected that electrical stimulation protocols used to study LTD and
patterns of LGN and cortical activity in vivo may be
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differentially susceptible to genetic or pharmacological manipulations.
Much stronger evidence has come from the study of
mediators of LTD. The most well-understood forms of
LTD in visual cortex require for induction activation
of NMDA receptors (Crozier et al., 2007; Kirkwood &
Bear, 1994), and it is now very well established that
NMDA receptor activation is also required for OD plasticity in visual cortex (Bear et al., 1990; Ramoa et al.,
2001). Even subtle manipulations of NMDA receptor
subunit composition similarly affect LTD and deprivedeye depression (Cho et al., 2009). A limitation on the
interpretation of these findings, however, is that NMDA
receptors trigger multiple forms of synaptic plasticity,
not just LTD.
As mentioned previously, one form of LTD is mediated by clathrin-dependent endocytosis of AMPA receptors, and loss of surface AMPA receptors has been
observed after MD. NMDA receptor–dependent AMPA
receptor endocytosis is selectively blocked by peptides
that mimic regions of the GluR2 subunit C-terminus
required for binding of clathrin adaptor proteins.
Recent studies have shown that expression of these
peptides in cortical neurons selectively prevents the
depression of deprived-eye responses after MD (Yang
et al., 2011; Yoon et al., 2009). Another requirement for
AMPA receptor endocytosis is expression of the immediate early gene Arc (Chowdhury et al., 2006), and
deprived-eye depression is absent in the Arc knockout
mouse (McCurry et al., 2010). These data provide
strong evidence that NMDA receptor–mediated
AMPA receptor endocytosis is a critical mediator of OD
plasticity.
Most of the aforementioned studies were focused on
plasticity in layer 4 of mouse visual cortex, because this
layer receives the bulk of the LGN input. However,
studies of plasticity in layer 3 (which also receives direct
LGN input in the mouse) have revealed an interesting
variation in the mechanism of LTD and OD plasticity.
Although LTD is still NMDA receptor–dependent in
layer 3, it is not mediated by AMPA receptor endocytosis. Rather, layer 3 LTD is mediated by a mechanism that
involves activation of presynaptic cannabinoid (CB)
receptors (Crozier et al., 2007). An inhibitor of CB1
receptors, AM251, reliably blocks layer 3 LTD, whereas
the GluR2 C-terminus peptides do not. In excellent
agreement with the “LTD hypothesis” of visual cortical
plasticity, OD plasticity in layer 3 (but not layer 4) is also
blocked by AM251. Together, these data show that the
earliest event in the development of amblyopia is LTD
of synaptic transmission caused by weak NMDA receptor activation in response to poorly structured activity
arising from the deprived eye.
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Structural Plasticity after MD
The following facts have been established: (1) Early
molecular changes modify the strength of synaptic
transmission soon after onset of MD, and (2) a longterm consequence of MD is structural modification of
geniculocortical synapses and axon arbors. The important questions remain as to how rapidly structural plasticity occurs and how this is related to early synaptic
plasticity.
Early anatomical studies of OD columns in kittens
seemed to indicate that OD plasticity is a consequence
of the modification of synapses in layer 4, where geniculocortical axons first exert their influence in visual
cortex. First visualized as eye-specific stripes in V1,
LeVay, Wiesel, and Hubel (1980) showed that the
shrinkage and expansion of deprived and nondeprived
thalamic afferents in layer 4 appear to faithfully and
clearly reflect the loss and gain of function of nondeprived and deprived inputs, respectively. It was also
noted that the degree of OD column plasticity matched
well with the age-related decrease in physiological plasticity (LeVay, Wiesel, & Hubel, 1980; Wiesel & Hubel,
1963a). These observations were sufficient to support
the view that the thalamocortical synapse was the site
for the initial plasticity. However, in searching for the
limits of the critical period, it was also noted that the
OD shift was only detected physiologically in superficial
layers when MD was initiated in greater than 1-year-old
monkeys (Blakemore, Garey, & Vital-Durand, 1978;
Hubel, Wiesel, & LeVay, 1977). Thus, structural plasticity of thalamocortical inputs is not necessary for the OD
shift under all conditions.
Nearly two decades later, Antonini and Stryker (1993)
demonstrated at the single-axon level that there was a
dramatic pruning of deprived-eye thalamocortical
axons after only 7 days of MD in kitten V1. However,
although more rapid than previously suspected, this
pruning was incomplete by 4 days post-MD, long after
saturation of the physiological OD shift within 2 days of
MD (Trachtenberg, Trepel, & Stryker, 2000). Thus,
even though early anatomical studies of OD columns in
kittens suggested that OD plasticity is indeed a consequence of the modification of synapses in layer 4, they
concluded that this was still too slow to account for or
contribute to the earliest functional consequences of
MD: a loss of visual function in the deprived-eye pathway.
Comparable studies in the mouse yielded a similar conclusion (Antonini, Fagiolini, & Stryker, 1999).
In a search for a faster anatomical correlate of OD
plasticity, Trachtenberg and Stryker (2001) showed that
anatomical rearrangements of long-range horizontal
connections in superficial layers were concurrent with
a 2-day OD shift in strabismic kittens, which was in line
with earlier studies showing that physiological measures
of OD plasticity revealed rapid OD shifts in layer 2/3
(Trachtenberg, Trepel, & Stryker, 2000). Whether
similar anatomical plasticity of intracortical axons
occurs in mouse visual cortex after 3 days of MD is
unknown. Again, because the mouse visual cortex lacks
OD columns, monitoring horizontal connectivity in a
meaningful way with regard to eye-specific function is
technically difficult. However, we can garner clues from
2-photon imaging studies of cortical axons in V1 during
functional reorganization induced by discrete retinal
lesions. These studies reveal a high capacity for the
rapid anatomical plasticity of intracortical axons, demonstrating the potential for such changes to contribute
to rapid functional reorganization in mouse (Keck
et al., 2011).
Relating Fine-Scale Structural Plasticity and
Rapid Functional Plasticity In order to establish
whether functional and structural plasticity are distinct
processes or part of a continuum, it is first necessary to
identify where synaptic rearrangements are concurrent
with deprived-eye depression. One approach to monitor
changes in connectivity in cortex is to examine dendritic spines, which serve as a proxy for observing
excitatory synapses (Holtmaat & Svoboda, 2009). The
majority of these structures receive axonal input from
other cortical neurons whereas a much smaller subset
(<10%) receive thalamocortical input (Ahmed et al.,
1994, 1997; da Costa & Martin, 2011). To date, there
are relatively few studies that have been designed to
examine spine turnover during brief MD in vivo, but
the results so far are consistent with a role for rapid
structural plasticity in deprived-eye depression. In
ferret, spine loss was observed in deprived-eye cortical
domains that underwent functional depression within
hours of MD (Yu, Majewska, & Sur, 2012). Accordingly,
in this same study, rapid spine growth was also observed
in deprived-eye cortical domains that showed functional
recovery when normal binocular vision was restored
after MD. In mouse, 4 days of MD increases the motility
of dendritic spines located in superficial layers belonging to layer 5 pyramidal neurons in mice (Oray,
Majewska, & Sur, 2004). In studies of fixed tissue,
Mataga, Mizuguchi, and Hensch (2004) reported a
transient decrease in spine density in layer 2/3 pyramidal cells in a confined 25-μm-long region of their proximal apical dendrites.
The rapid, MD-induced changes in dendritic spine
dynamics found in mouse V1 are dependent on the
tissue-type plasminogen activator (tPA)/plasmin proteolytic cascade. Brief MD elevates tPA activity in the
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Only recently has it been possible to examine the
state of thalamocortical synapses within the time frame
of maximal deprived-eye depression (3 days post-MD in
mouse). Capitalizing on the discovery that the VGluT2
vesicular glutamate transporter is selectively localized to
thalamocortical terminals (Nahmani & Erisir, 2005), we
quantified the density of thalamocortical synaptic terminals in layer 4 of mouse V1 after 3 and 7 days of MD
(Coleman et al., 2010) (see figure 100.2A–E). Both the
density and size of synaptic terminals in layer 4 were
decreased within 3 days of MD (see figure 100.2F–G).
These findings are consistent with previous work
showing that thalamocortical synaptic terminals exhibit
morphological signatures of retraction and weakening
after long-term MD (Tieman, 1984), but on a time scale
that matches maximal deprived-eye depression (see
figure 100.2H). It is also interesting to note that, like
physiological OD plasticity, these anatomical correlates
of modified thalamocortical transmission are a consequence of uncorrelated ascending activity rather than
an absence of retinal activity, suggesting that common
cellular-level mechanisms are at work (Coleman et al.,
2010).
These synapse-scale structural responses to MD are
entirely consistent with the hypothesis that deprived-eye
depression (and loss of visual function in amblyopia)
occurs through LTD mechanisms. It has been shown
that LTD is associated with structural reorganization of
presynaptic axonal boutons and a retraction of dendritic spines (Bastrikova et al., 2008; Nagerl et al., 2004;
Zhou, Homma, & Poo, 2004).
How can fine-scale structural changes in mice be reconciled with the comparatively slower retraction of
entire deprived-eye thalamocortical axons observed in
kittens? The earliest time anyone has assayed for thalamocortical axon changes after MD in the mouse visual
cortex is 20 days, wherein no significant difference was
found between the complexity of deprived-eye and
open-eye arbors reconstructed from both hemispheres
of the same animal (Antonini, Fagiolini, & Stryker,
1999). This observation does not preclude more discrete changes along individual branches of thalamocortical arbors in response to MD however, which
could be obscured by the heterogeneous structure of
contralateral-eye axons or the intermingling of OD
within layer 4 of mouse V1 (Bence & Levelt, 2005).
Although smaller scale remodeling of axonal branches
may be difficult to detect, it is reasonable to expect such
changes based on the synaptic loss found in the ultrastructural studies described above.
What is the anatomical scale of the physical reorganization, if any, of axons after 3 days of MD? We have
begun to test the hypothesis that some portion of
thalamocortical axonal branches reorganize fast enough
to contribute to deprived-eye depression using 2-photon
laser-scanning microscopy (see figure 100.3A). Nearly
all 2-photon imaging studies in sensory cortex have
been limited to superficial layers because the resolution
is relatively poor in deeper layers of V1 (i.e., ~400–
500 μm to reach layer 4). However, an advantage of the
mouse visual system is that the same thalamocortical
axons projecting to layer 4 send significant collaterals
to layers 1–3 as well (see figure 100.3B; Antonini,
Fagiolini, & Stryker, 1999; Rubio-Garrido et al., 2009).
As shown in figure 100.3B–D, thalamocortical branches
of deprived-eye axons can be labeled with GFP and
tracked in layer 1 before and after MD. In the example
images, two branch tips of an axon show significant
retractions during the first 3 days of MD with no further
changes during an additional 4 days of MD.
While more work is clearly needed, the observations
described here reveal that branch remodeling on the
order of tens to hundreds of micrometers, as well as
changes in dendritic spine structure and number,
rapidly occur in visual cortex at an age when deprivedeye depression is robust. In addition to dendritic spines,
terminal and en passant bouton dynamics can also be
monitored and provide a reliable proxy for visualizing
synaptic turnover in vivo (De Paola et al., 2006; Gogolla,
Galimberti, & Caroni, 2007). Recent advances in the
tools used for labeling and imaging cells in vivo have
given us a greater appreciation for how even relatively subtle changes in synaptic structures can significantly alter cortical function (Gogolla, Galimberti, &
Caroni, 2007; Holtmaat & Svoboda, 2009; Hubener &
Bonhoeffer, 2010). With these tools, we are now poised
to investigate the relationship between “functional” and
“structural” plasticity in the context of OD plasticity
with greater temporal and spatial precision than in the
past.
Future Challenges
While much progress has been made toward unveiling
the molecular and anatomical substrates of OD plasticity, several questions remain unanswered. What is the
functional impact of relatively small-scale changes to
thalamocortical synapses? What is the threshold for the
amount of synapse loss required to alter the receptive
field properties of an individual visually driven neuron?
Are LTD mechanisms required for rapid structural plasticity of corticocortical and/or thalamocortical connections? Does the disruption of structural plasticity alone
interfere with or diminish functional plasticity or visually guided behavior? What lessons can be learned from
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our current understanding of OD plasticity to facilitate
recovery of visual function in amblyopia?
A long-standing challenge in the field has been to
clearly label eye-specific inputs into the cortex in living
tissue. Without this information it is difficult to interpret many of the results in the literature. For example,
MD produces changes in dendritic spines (Mataga,
Mizuguchi, & Hensch, 2004; Oray, Majewska, & Sur,
2004), but it is unclear whether these changes are
restricted to spines receiving input from a particular
eye. Similarly, studies of thalamocortical synaptic terminals in mice have been limited to examining net changes
to these inputs because the eye-specificity of these afferents cannot be determined. In contrast, one can ascertain precisely what synapses are modified if specific
populations of axons are selectively labeled and monitored. New virus-based tools for anterograde transsynaptic labeling of axons and genetic manipulation of
eye-specific pathways may provide a long sought after
solution to this challenge (Beier et al., 2011; Gradinaru
et al., 2010). With this technology, one could test the
prediction that occlusion of LTD by prior MD (Crozier
et al., 2007) is restricted to deprived-eye, but not openeye, inputs into layer 4. Likewise, one could monitor
open-eye thalamocortical axons to determine whether
growth of these axons and synapses contributes to
open-eye potentiation, as suggested from previous
studies (Coleman et al., 2010). Furthermore, eyespecific synapses could be manipulated and/or labeled
using transsynaptic viruses that allow for perturbations
of connected cells during the OD shift and/or expression of genetically encoded molecules for visualizing
synapse loss and gain in situ with high fidelity (Kim
et al., 2012).
To better understand how synapse remodeling affects
cellular function, the development of combinatorial
approaches for simultaneously monitoring neural
anatomy and function during MD are needed. Recent
studies suggest it may soon be feasible to map functionally defined afferent inputs with single-synapse resolution (Chen et al., 2011; Jia et al., 2010). In addition,
advances in genetically encoded calcium sensors may
permit large numbers of neurons (along with their
axons, dendrites, and spines) to be observed repeatedly
over the course of MD (Looger & Griesbeck, 2012; Tian
et al., 2012). Specifically, the addition of improved
intensio- and ratiometric calcium sensors (e.g., GCaMP3
and YC3.6, respectively) to the imager’s toolbox may
make these experiments feasible (Andermann, Kerlin,
& Reid, 2010; Andermann et al., 2012; Lutcke et al.,
2010; Tian et al., 2009). Together, these advances could
open the door to investigating the contribution of specific synapses to OD plasticity and whether individual
neurons in a cortical network respond to MD in a cellautonomous manner.
Further work is needed to determine whether any
form of structural plasticity during MD requires LTD
mechanisms. For example, as highlighted in figure
100.3B, a simple experiment would be to determine
whether structural changes to axon branches in layer 1
require CB receptor activation or clathrin-mediated
AMPA receptor trafficking in a manner similar to
deprived-eye depression. Reagents that disrupt structural changes, but not physiological processes, would
help establish a causal role of anatomical plasticity in
experience-dependent plasticity. While it is not known
whether open-eye potentiation mirrors deprived-eye
depression by using LTP-like mechanisms, there is some
indication that the former may be supported by different molecular players (Kaneko et al., 2008; Ranson et
al., 2012). Given that MD affects both deprived-eye as
well as open-eye responses, it is critical to determine if
alterations in spine dynamics associated with MD relate
to the depression or potentiation of visual responses.
There is already convincing evidence that the rapid
growth of new spines provides a substrate for strengthening open-eye connections (Yu, Majewska, & Sur,
2012). Likewise, if the model we propose in figure
100.2H is correct, the growth of new open-eye thalamocortical synapses may provide a means for increasing
the strength of this input (Coleman et al., 2010). It will
be important to follow up these findings by simultaneously imaging axons and spines in in vivo longitudinal
studies of structure. Techniques that would allow one
to ablate new synaptic growth or selectively block structural plasticity altogether while monitoring cellular
function would provide valuable insights into the contribution of anatomical plasticity to functional changes.
Finally, previous studies using the so-called “reversesuture” paradigm show that weakening of previously
open-eye synapses occurs readily whereas strengthening
of previously deprived-eye synapses is modest, with little
to no sign of recovery at the level of thalamocortical
axons (Antonini et al., 1998). Thus, rejuvenating structural plasticity may lead to a more complete functional
recovery in amblyopia. It is important to understand
whether structural plasticity is causal to other forms of
experience-dependent plasticity known to enhance cortical function, as these paradigms may offer opportunities to investigate ways to restore structural connectivity.
For example, functional and structural recovery from
deprivation amblyopia can be dramatically improved
when reverse suture is preceded by brief periods of dark
adaptation (He et al., 2007; Montey & Quinlan, 2011).
Interestingly, both dark adaptation and treatment with
fluoxetine show a capacity for reactivating structural
The Molecular and Structural Basis of Amblyopia
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plasticity in the adult visual cortex following MD (Chen
et al., 2011; Montey & Quinlan, 2011). However, the
kinetics of thalamocortical axon plasticity or eyespecific postsynaptic morphological plasticity have not
been examined during open-eye potentiation and
warrant investigation. Therapeutic strategies that capitalize on knowledge of experience-dependent plasticity
during development and/or perceptual learning have
high potential. Increasing visual function through
mechanisms of perceptual learning (Cooke & Bear,
2010; Sale et al., 2010) and pharmacological interventions that facilitate deprived-eye recovery (Baroncelli,
Maffei, & Sale, 2011; Maya Vetencourt et al., 2008; Yang
et al., 2011) are beginning to show promise in humans
(Levi & Li, 2009; Maurer & Hensch, 2012).
In conclusion, studies of OD plasticity in mouse visual
cortex have improved our understanding of the detailed
sequence of events that culminate in the physical
disconnection of visual inputs from their targets in V1
after MD. The knowledge of how experiencedependent structural changes overlap or connect with
molecular cascades associated with LTD will aid in the
development of novel interventions for amblyopia that
either strengthen remaining inputs or restore those
connections that were lost (Cho & Bear, 2010; Smith,
Heynen, & Bear, 2009).
Acknowledgments
We thank Sam Cooke, Lena Khibnik, Rachel Schecter,
and Sue Semple-Rowland for helpful discussions and
comments and Lauren Herring, Suzanne Meagher, and
Erik Sklar for excellent technical assistance.
References
K2
Ahmed, B., Anderson, J. C., Douglas, R. J., Martin, K. A., &
Nelson, J. C. (1994). Polyneuronal innervation of spiny
stellate neurons in cat visual cortex. Journal of Comparative
Neurology, 341, 39–49.
Ahmed, B., Anderson, J. C., Martin, K. A., & Nelson, J. C.
(1997). Map of the synapses onto layer 4 basket cells of the
primary visual cortex of the cat. Journal of Comparative Neurology, 380, 230–242.
Andermann, M. L., Kerlin, A. M., & Reid, R. C. (2010).
Chronic cellular imaging of mouse visual cortex during
operant behavior and passive viewing. Frontiers in Cellular
Neuroscience, 4, 3.
Andermann, M. L., Kerlin, A. M., Roumis, D. K., Glickfeld,
L. L., & Reid, R. C. (2012). Functional specialization of
mouse higher visual cortical areas. Neuron, 72, 1025–1039.
Antonini, A., & Stryker, M. P. (1993). Rapid remodeling of
axonal arbors in the visual cortex. Science, 260, 1819–1821.
Antonini, A., Fagiolini, M., & Stryker, M. P. (1999). Anatomical correlates of functional plasticity in mouse visual cortex.
Journal of Neuroscience, 19, 4388–4406.
1442
Antonini, A., Gillespie, D. C., Crair, M. C., & Stryker, M. P.
(1998). Morphology of single geniculocortical afferents
and functional recovery of the visual cortex after reverse
monocular deprivation in the kitten. Journal of Neuroscience,
18, 9896–9909.
Baroncelli, L., Maffei, L., & Sale, A. (2011). New perspectives
in amblyopia therapy on adults: A critical role for the excitatory/inhibitory balance. Frontiers in Cellular Neuroscience, 5,
1–6.
Bastrikova, N., Gardner, G. A., Reece, J. M., Jeromin, A., &
Dudek, S. M. (2008). Synapse elimination accompanies
functional plasticity in hippocampal neurons. Proceedings of
the National Academy of Sciences of the United States of America,
105, 3123–3127. doi:10.1073/pnas.0800027105.
Bear, M. F. (2003). Bidirectional synaptic plasticity: From
theory to reality. Philosophical Transactions of the Royal
Society of London. Series B, Biological Sciences, 358,
649–655.
Bear, M. F., Kleinschmidt, A., Gu, Q. A., & Singer, W. (1990).
Disruption of experience-dependent synaptic modifications in striate cortex by infusion of an NMDA receptor
antagonist. Journal of Neuroscience, 10, 909–925.
Beier, K. T., Saunders, A., Oldenburg, I. A., Miyamichi, K.,
Akhtar, N., Luo, L., et al. (2011). Anterograde or retrograde transsynaptic labeling of CNS neurons with vesicular
stomatitis virus vectors. Proceedings of the National Academy of
Sciences of the United States of America, 108, 15414–15419.
doi:10.1073/pnas.1110854108.
Bence, M., & Levelt, C. N. (2005). Structural plasticity in the
developing visual system. Progress in Brain Research, 147,
125–139.
Blakemore, C., Garey, L. J., & Vital-Durand, F. (1978). The
physiological effects of monocular deprivation and their
reversal in the monkey’s visual cortex. Journal of Physiology,
283, 223–262.
Chen, J. L., Lin, W. C., Cha, J. W., So, P. T., Kubota, Y., &
Nedivi, E. (2011). Structural basis for the role of inhibition
in facilitating adult brain plasticity. Nature Neuroscience, 14,
587–594.
Chen, X., Leischner, U., Rochefort, N. L., Nelken, I., &
Konnerth, A. (2011). Functional mapping of single spines
in cortical neurons in vivo. Nature, 475, 501–505.
Cho, K. K., & Bear, M. F. (2010). Promoting neurological
recovery of function via metaplasticity. Future Neurology, 5,
21–26.
Cho, K. K., Khibnik, L., Philpot, B. D., & Bear, M. F. (2009).
The ratio of NR2A/B NMDA receptor subunits determines
the qualities of ocular dominance plasticity in visual cortex.
Proceedings of the National Academy of Sciences of the United
States of America, 106, 5377–5382. doi:10.1073/pnas.0808104
106.
Choi, S. Y., Morales, B., Lee, H. K., & Kirkwood, A. (2002).
Absence of long-term depression in the visual cortex of
glutamic acid decarboxylase-65 knock-out mice. Journal of
Neuroscience, 22, 5271–5276.
Chowdhury, S., Shepherd, J. D., Okuno, H., Lyford, G., Petralia, R. S., Plath, N., et al. (2006). Arc/Arg3.1 interacts with
the endocytic machinery to regulate AMPA receptor trafficking. Neuron, 52, 445–459. doi:10.1016/j.neuron.2006.08.
033.
Coleman, J. E., Law, K., & Bear, M. F. (2009). Anatomical
origins of ocular dominance in mouse primary visual
cortex. Neuroscience, 161, 561–571.
Jason E. Coleman, Arnold J. Heynen, and Mark F. Bear
Werner—The New Visual Neurosciences
8857_100.indd 1442
4/26/2013 6:48:28 PM
PROPERTY OF MIT PRESS: FOR PROOFREADING AND INDEXING PURPOSES ONLY
Coleman, J. E., Nahmani, M., Gavornik, J. P., Haslinger, R.,
Heynen, A. J., Erisir, A., et al. (2010). Rapid structural
remodeling of thalamocortical synapses parallels experience-dependent functional plasticity in mouse primary
visual cortex. Journal of Neuroscience, 30, 9670–9682.
doi:10.1523/JNEUROSCI.1248-10.2010.
Cooke, S. F., & Bear, M. F. (2010). Visual experience induces
long-term potentiation in the primary visual cortex. Journal
of Neuroscience, 30, 16304–16313.
Crair, M. C., Horton, J. C., Antonini, A., & Stryker, M. P.
(2001). Emergence of ocular dominance columns in cat
visual cortex by 2 weeks of age. Journal of Comparative Neurology, 430, 235–249.
Crowley, J. C., & Katz, L. C. (2000). Early development of
ocular dominance columns. Science, 290, 1321–1324.
Crozier, R. A., Wang, Y., Liu, C. H., & Bear, M. F. (2007).
Deprivation-induced synaptic depression by distinct mechanisms in different layers of mouse visual cortex. Proceedings
of the National Academy of Sciences of the United States of America,
104, 1383–1388.
da Costa, N. M., & Martin, K. A. (2011). How thalamus connects to spiny stellate cells in the cat’s visual cortex. Journal
of Neuroscience, 31, 2925–2937.
De Paola, V., Holtmaat, A., Knott, G., Song, S., Wilbrecht, L.,
Caroni, P., et al. (2006). Cell type–specific structural plasticity of axonal branches and boutons in the adult neocortex.
Neuron, 49, 861–875. doi:10.1016/j.neuron.2006.02.017.
Doshi, N. R., & Rodriguez, M. L. (2007). Amblyopia. American
Family Physician, 75, 361–367.
Dudek, S. M., & Bear, M. F. (1992). Homosynaptic long-term
depression in area CA1 of hippocampus and effects of
N-methyl-D-aspartate receptor blockade. Proceedings of the
National Academy of Sciences of the United States of America, 89,
4363-4367.
Frenkel, M. Y., & Bear, M. F. (2004). How monocular deprivation shifts ocular dominance in visual cortex of young mice.
Neuron, 44, 917–923.
Gogolla, N., Galimberti, I., & Caroni, P. (2007). Structural
plasticity of axon terminals in the adult. Current Opinion in
Neurobiology, 17, 516–524.
Gradinaru, V., Zhang, F., Ramakrishnan, C., Mattis, J., Prakash,
R., Diester, I., et al. (2010). Molecular and cellular
approaches for diversifying and extending optogenetics.
Cell, 141, 154–165. doi:10.1016/j.cell.2010.02.037.
He, H. Y., Ray, B., Dennis, K., & Quinlan, E. M. (2007). Experience-dependent recovery of vision following chronic
deprivation amblyopia. Nature Neuroscience, 10, 1134–1136.
Hensch, T. K., Fagiolini, M., Mataga, N., Stryker, M. P.,
Baekkeskov, S., & Kash, S. F. (1998). Local GABA circuit
control of experience-dependent plasticity in developing
visual cortex. Science, 282, 1504–1508.
Heynen, A. J., Yoon, B. J., Liu, C. H., Chung, H. J., Huganir,
R. L., & Bear, M. F. (2003). Molecular mechanism for loss
of visual cortical responsiveness following brief monocular
deprivation. Nature Neuroscience, 6, 854–862.
Hofer, S. B., Mrsic-Flogel, T. D., Bonhoeffer, T., & Hubener,
M. (2006). Prior experience enhances plasticity in adult
visual cortex. Nature Neuroscience, 9, 127–132.
Holmes, J. M., & Clarke, M. P. (2006). Amblyopia. Lancet, 367,
1343–1351. doi: 101016/S0140–6736(06)68581–4.
Holtmaat, A., & Svoboda, K. (2009). Experience-dependent
structural synaptic plasticity in the mammalian brain. Nature
Reviews. Neuroscience, 10, 647–658.
Horton, J. C., & Adams, D. L. (2005). The cortical column: A
structure without a function. Philosophical Transactions of the
Royal Society of London. Series B, Biological Sciences, 360, 837–
862.
Hubel, D. H., & Wiesel, T. N. (1964). Effects of monocular
deprivation in kittens. Naunyn-Schmiedebergs Archiv fur Experimentelle Pathologie und Pharmakologie, 248, 492–497.
Hubel, D. H., & Wiesel, T. N. (1968). Receptive fields and
functional architecture of monkey striate cortex. Journal of
Physiology, 195, 215–243.
Hubel, D. H., Wiesel, T. N., & LeVay, S. (1977). Plasticity of
ocular dominance columns in monkey striate cortex. Philosophical Transactions of the Royal Society of London. Series B,
Biological Sciences, 278, 377–409.
Hubener, M., & Bonhoeffer, T. (2010). Searching for engrams.
Neuron, 67, 363–371.
Iny, K., Heynen, A. J., Sklar, E., & Bear, M. F. (2006). Bidirectional modifications of visual acuity induced by monocular
deprivation in juvenile and adult rats. Journal of Neuroscience,
26, 7368–7374.
Jia, H., Rochefort, N. L., Chen, X., & Konnerth, A. (2010).
Dendritic organization of sensory input to cortical neurons
in vivo. Nature, 464, 1307–1312.
Kaneko, M., Stellwagen, D., Malenka, R. C., & Stryker, M. P.
(2008). Tumor necrosis factor-alpha mediates one component of competitive, experience-dependent plasticity in
developing visual cortex. Neuron, 58, 673–680.
Keck, T., Scheuss, V., Jacobsen, R. I., Wierenga, C. J., Eysel,
U. T., Bonhoeffer, T., et al. (2011). Loss of sensory input
causes rapid structural changes of inhibitory neurons in
adult mouse visual cortex. Neuron, 71, 869–882. doi:10.1016/j.
neuron.2011.06.034.
Khibnik, L. A., Cho, K. K., & Bear, M. F. (2010). Relative contribution of feedforward excitatory connections to expression of ocular dominance plasticity in layer 4 of visual
cortex. Neuron, 66, 493–500.
Kim, J., Zhao, T., Petralia, R. S., Yu, Y., Peng, H., Myers, E.,
et al. (2012). mGRASP enables mapping mammalian synaptic connectivity with light microscopy. Nature Methods, 9,
96–102. doi:10.1038/nmeth.1784.
Kirkwood, A., & Bear, M. F. (1994). Homosynaptic long-term
depression in the visual cortex. Journal of Neuroscience, 14,
3404–3412.
LeVay, S., Stryker, M. P., & Shatz, C. J. (1978). Ocular dominance columns and their development in layer IV of the
cat’s visual cortex: A quantitative study. Journal of Comparative Neurology, 179, 223–244.
LeVay, S., Wiesel, T. N., & Hubel, D. H. (1980). The development of ocular dominance columns in normal and visually
deprived monkeys. Journal of Comparative Neurology, 191, 1–
51.
Levi, D. M., & Li, R. W. (2009). Improving the performance
of the amblyopic visual system. Philosophical Transactions of
the Royal Society of London. Series B, Biological Sciences, 364,
399–407.
Looger, L. L., & Griesbeck, O. (2012). Genetically encoded
neural activity indicators. Current Opinion in Neurobiology, 22,
18–23.
Lutcke, H., Murayama, M., Hahn, T., Margolis, D. J., Astori,
S., Zum Alten Borgloh, S. M., et al. (2010). Optical recording of neuronal activity with a genetically-encoded calcium
indicator in anesthetized and freely moving mice. Frontiers
in Neural Circuits, 4, 9.1–12. doi:10.3389/fncir.2010.00009.
The Molecular and Structural Basis of Amblyopia
1443
Werner—The New Visual Neurosciences
8857_100.indd 1443
4/26/2013 6:48:29 PM
K2
PROPERTY OF MIT PRESS: FOR PROOFREADING AND INDEXING PURPOSES ONLY
Malenka, R. C., & Bear, M. F. (2004). LTP and LTD: An embarrassment of riches. Neuron, 44, 5–21.
Mataga, N., Mizuguchi, Y., & Hensch, T. K. (2004). Experience-dependent pruning of dendritic spines in visual cortex
by tissue plasminogen activator. Neuron, 44, 1031–1041.
Mataga, N., Nagai, N., & Hensch, T. K. (2002). Permissive
proteolytic activity for visual cortical plasticity. Proceedings of
the National Academy of Sciences of the United States of America,
99, 7717–7721. doi:10.1073/pnas.102088899.
Maurer, D., & Hensch, T. K. (2012). Amblyopia: Background
to the special issue on stroke recovery. Developmental Psychobiology, 54, 224–238.
Maya Vetencourt, J. F., Sale, A., Viegi, A., Baroncelli, L., De
Pasquale, R., O’Leary, O. F., et al. (2008). The antidepressant fluoxetine restores plasticity in the adult visual cortex.
Science, 320, 385–388. doi:10.1126/science.1150516.
McCurry, C. L., Shepherd, J. D., Tropea, D., Wang, K. H., Bear,
M. F., & Sur, M. (2010). Loss of Arc renders the visual cortex
impervious to the effects of sensory experience or deprivation. Nature Neuroscience, 13, 450–457.
Mioche, L., & Singer, W. (1989). Chronic recordings from
single sites of kitten striate cortex during experiencedependent modifications of receptive-field properties.
Journal of Neurophysiology, 62, 185–197.
Montey, K. L., & Quinlan, E. M. (2011). Recovery from
chronic monocular deprivation following reactivation of
thalamocortical plasticity by dark exposure. Nature Communications, 2, 317.
Mrsic-Flogel, T. D., Hofer, S. B., Ohki, K., Reid, R. C.,
Bonhoeffer, T., & Hubener, M. (2007). Homeostatic regulation of eye-specific responses in visual cortex during ocular
dominance plasticity. Neuron, 54, 961–972.
Nagerl, U. V., Eberhorn, N., Cambridge, S. B., & Bonhoeffer,
T. (2004). Bidirectional activity-dependent morphological
plasticity in hippocampal neurons. Neuron, 44, 759–767.
Nahmani, M., & Erisir, A. (2005). VGluT2 immunochemistry
identifies thalamocortical terminals in layer 4 of adult and
developing visual cortex. Journal of Comparative Neurology,
484, 458–473.
Oray, S., Majewska, A., & Sur, M. (2004). Dendritic spine
dynamics are regulated by monocular deprivation and
extracellular matrix degradation. Neuron, 44, 1021–1030.
Prusky, G. T., West, P. W., & Douglas, R. M. (2000). Experience-dependent plasticity of visual acuity in rats. European
Journal of Neuroscience, 12, 3781–3786.
Ramoa, A. S., Mower, A. F., Liao, D., & Jafri, S. I. (2001). Suppression of cortical NMDA receptor function prevents
development of orientation selectivity in the primary visual
cortex. Journal of Neuroscience, 21, 4299–4309.
Ranson, A., Cheetham, C. E., Fox, K., & Sengpiel, F. (2012).
Homeostatic plasticity mechanisms are required for juvenile, but not adult, ocular dominance plasticity. Proceedings
of the National Academy of Sciences of the United States of America,
109, 1311–1316.
Rittenhouse, C. D., Shouval, H. Z., Paradiso, M. A., & Bear,
M. F. (1999). Monocular deprivation induces homosynaptic
long-term depression in visual cortex. Nature, 397, 347–350.
Rittenhouse, C. D., Siegler, B. A., Voelker, C. C., Shouval, H.
Z., Paradiso, M. A., & Bear, M. F. (2006). Stimulus for rapid
ocular dominance plasticity in visual cortex. Journal of Neurophysiology, 95, 2947–2950.
Rubio-Garrido, P., Perez-de-Manzo, F., Porrero, C., Galazo,
M. J., & Clasca, F. (2009). Thalamic input to distal apical
dendrites in neocortical layer 1 is massive and highly convergent. Cerebral Cortex, 19, 2380–2395.
Sale, A., De Pasquale, R., Bonaccorsi, J., Pietra, G., Olivieri,
D., Berardi, N., et al. (2010). Visual perceptual learning
induces long-term potentiation in the visual cortex. Neuroscience,
172,
219–225.
doi:10.1016/j.neuroscience.2010.10.078.
Smith, G. B., Heynen, A. J., & Bear, M. F. (2009). Bidirectional
synaptic mechanisms of ocular dominance plasticity in
visual cortex. Philosophical Transactions of the Royal Society of
London. Series B, Biological Sciences, 364, 357–367.
Steele, P. M., & Mauk, M. D. (1999). Inhibitory control of LTP
and LTD: Stability of synapse strength. Journal of Neurophysiology, 81, 1559–1566.
Tian, L., Akerboom, J., Schreiter, E. R., & Looger, L. L. (2012).
Neural activity imaging with genetically encoded calcium
indicators. Progress in Brain Research, 196, 79–94.
Tian, L., Hires, S. A., Mao, T., Huber, D., Chiappe, M. E.,
Chalasani, S. H., et al. (2009). Imaging neural activity in
worms, flies and mice with improved GCaMP calcium indicators. Nature Methods, 6, 875–881. doi:10.1038/nmeth.1398.
Tieman, S. B. (1984). Effects of monocular deprivation on
geniculocortical synapses in the cat. Journal of Comparative
Neurology, 222, 166–176.
Trachtenberg, J. T., & Stryker, M. P. (2001). Rapid anatomical
plasticity of horizontal connections in the developing visual
cortex. Journal of Neuroscience, 21, 3476–3482.
Trachtenberg, J. T., Trepel, C., & Stryker, M. P. (2000). Rapid
extragranular plasticity in the absence of thalamocortical
plasticity in the developing primary visual cortex. Science,
287, 2029–2032.
Wiesel, T. N., & Hubel, D. H. (1963a). Effects of visual deprivation on morphology and physiology of cells in the cat’s
lateral geniculate body. Journal of Neurophysiology, 26, 978–
993.
Wiesel, T. N., & Hubel, D. H. (1963b). Single-cell responses
in striate cortex of kittens deprived of vision in one eye.
Journal of Neurophysiology, 26, 1003–1017.
Yang, K., Xiong, W., Yang, G., Kojic, L., Wang, Y. T., & Cynader,
M. (2011). The regulatory role of long-term depression in
juvenile and adult mouse ocular dominance plasticity. Scientific Reports, 1, 203.
Yoon, B. J., Smith, G. B., Heynen, A. J., Neve, R. L., & Bear,
M. F. (2009). Essential role for a long-term depression
mechanism in ocular dominance plasticity. Proceedings of the
National Academy of Sciences of the United States of America, 106,
9860–9865. doi:10.1073/pnas.0901305106.
Yu, H., Majewska, A. K., & Sur, M. (2012). Rapid experiencedependent plasticity of synapse function and structure in
ferret visual cortex in vivo. Proceedings of the National Academy
of Sciences of the United States of America, 108, 21235–21240.
doi:10.1073/pnas.1108270109.
Zhou, Q., Homma, K. J., & Poo, M. M. (2004). Shrinkage of
dendritic spines associated with long-term depression of
hippocampal synapses. Neuron, 44, 749–757.
K2
1444
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Werner—The New Visual Neurosciences
8857_100.indd 1444
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