Progress in Brain Research, Vol. 147
ISSN 0079-6123
Copyright ß 2005 Elsevier BV. All rights reserved
CHAPTER 9
Excitatory–inhibitory balance and critical period
plasticity in developing visual cortex
Takao K. Hensch* and Michela Fagiolini
Laboratory for Neuronal Circuit Development, Critical Period Mechanisms Research Group, RIKEN Brain Science Institute,
2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
Introduction
loss of responsiveness to an eye deprived of vision in
the primary visual cortex of kittens. As a direct
behavioral consequence, the deprived eye becomes
amblyopic: its visual acuity is strongly reduced and
its contrast sensitivity blunted (see Daw, 1995).
Moreover, the rapid physiological effects of monocular deprivation (MD) are soon accompanied by an
anatomical reduction in size of horizontal connections and thalamic afferents serving the deprived eye
(Antonini and Stryker, 1993; Trachtenberg and
Stryker, 2001). Altogether these processes depend
upon competitive interactions between the two eyes
for the control of cortical territory. When both eyes
are sutured, no imbalance of input occurs and neither
eye loses the relative ability to drive visual responses
(Daw, 1995; Antonini and Stryker, 1998).
Importantly, a shift in ocular dominance toward
the open eye occurs only during a transient developmental critical period. Since Hubel and Wiesel’s
seminal work, the rules of activity-dependent competition and timing have been confirmed across a variety
of species. Interestingly, the duration of the critical
period appears to be tightly linked to the average life
expectancy for each mammal studied (Berardi et al.,
2000). In rodents as well as in cats (Fagiolini et al.,
1994; Daw, 1995; Gordon and Stryker, 1996),
plasticity is low at eye opening, peaks around four
weeks of age, and declines over several weeks to
months. Notably, the critical period is not a simple,
age-dependent maturational process, but rather a
series of events itself controlled in a use-dependent
Neuronal circuits are shaped by their activity during
‘‘critical’’ or ‘‘sensitive periods’’ in development.
Initially spontaneous, then early sensory-evoked
patterns of action potentials, are required to sculpt
the remarkably complex connectivity found in the
adult brain, which then loses this extraordinary level
of plasticity. Whether it is the targeting of individual
axons or the acquisition of language, there is no
doubt that dramatic re-wiring is most powerful early
in postnatal life. Despite decades of similar robust
observations across a wide spectrum of brain
functions, only recently have we begun to understand
the cellular basis that may underlie this fundamental
process. The ability to freely switch on or off critical
period mechanisms confirms the very existence of
such special stages of heightened plasticity. Here, we
focus on a newfound perspective of excitatoryinhibitory balance within cortical circuits that has
finally granted this control.
Visual cortex as a model system
The premier physiological model of critical period
plasticity is the developing visual system. Over 40
years ago, Wiesel and Hubel (1963) first described the
*Corresponding author. Tel.: +81-48-467-9634;
Fax: +81-48-467-2306; E-mail: [email protected]
DOI: 10.1016/S0079-6123(04)47009-5
115
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manner. Animals reared in complete darkness from
birth express a delayed profile with plasticity persisting into adulthood (Cynader, 1983; Mower, 1991).
The mouse visual cortex offers tremendous
advantages for developmental analysis, despite the
largely nocturnal lifestyle of rodents. Born with an
innate contralateral bias, their laterally displaced
eyes drive a robust, competition within a small,
binocular zone of primary visual cortex during a
short, two-week critical period, which can be delayed
by dark-rearing (Fig. 1) (Fagiolini et al., 1994;
Gordon and Stryker, 1996; Fagiolini et al., 2003).
The shift of responsiveness is reflected in a reduced
behavioral visual acuity through the closed eye
during a critical period identical to that measured by
single-unit electrophysiology (Prusky and Douglas,
2003). Anatomical correlates also follow the rapid
physiological changes in response to MD (Antonini
et al., 1999).
The restricted spatio-temporal dimensions in an
animal model of short gestation and large litter size
are ideal for dissecting the cellular and molecular
mechanisms of plasticity onset and closure.
Moreover, the power of genetic manipulation offers
a specificity of molecular control unprecedented by
pharmacological approaches in the cat or monkey.
Manipulating excitatory-inhibitory balance in vivo
Despite a wealth of phenomenology regarding the
rules of experience-dependent development (see Daw,
1995), precious little is known about the underlying
cellular mechanism. Over the years, a popular model
Fig. 1. Critical period plasticity in mouse visual cortex. The typical response bias toward contralateral eye input (ocular dominance
groups 1–3) in the binocular zone of rodents is robustly shifted in favor of the open ipsilateral eye (groups 5–7) following monocular
deprivation (MD) during the critical period (CP). Histograms are quantified as a weighted average (contralateral bias index, CBI),
which ranges from 0 to 1 for complete ipsilateral or contralateral eye dominance, respectively. One week after eye-opening at P14,
sensitivity to brief MD rapidly appears and persists for about two weeks, as measured by single-unit recording. The immature pre-CP
(pCP) phase is prolonged by dark-rearing from birth, such that the overall profile is delayed to yield plasticity in adulthood, as shown
previously for cats (Mower, 1991). Shaded region, range of nondeprived wild-type mice. Some error bars smaller than symbol size.
Data adapted from Gordon and Stryker (1996); Fagiolini et al. (2003); Iwai et al. (2003).
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of homosynaptic plasticity has emerged in parallel
studies of learning and memory primarily in the
hippocampus. While it is attractive to think of loss of
deprived-eye input as a long-term depression (LTD)
or gain of open-eye input as long-term potentiation
(LTP), advancing knowledge of their molecular
mechanism in vitro (Sanes and Lichtman, 1999) has
so far failed to predictably alter the critical period.
Disruption of tetanus-induced LTP or low-frequency
induced LTD has been dissociated from ocular
dominance plasticity on numerous occasions (see
Hensch, 2003). At the very least, we have learned that
cortical plasticity in the intact animal is not easily
explained by artificial stimulus protocols used to
adjust individual glutamatergic synapses in brain
slices. In retrospect, this is not surprising, because
unlike motor axons competing for a single target
muscle fiber, sensory input to the neocortex must first
be integrated by complex local circuit interactions
in vivo.
We therefore formulated the hypothesis that local
excitatory and inhibitory cortical circuits reach an
optimal balance only once in life during which
plasticity may occur. If correct, direct manipulation
of either excitation or inhibition should profoundly
affect the sensitivity to sensory deprivation. Previous
pharmacological attempts to disrupt the balance
grossly hyper-excited or shut down the cortex (Shaw
and Cynader, 1984;Videen et al., 1986; Ramoa et al.,
1988; Reiter and Stryker, 1988), yielding little insight
into the normal function of local circuits during
plasticity. Taking advantage of gene-targeting
technology, we instead attempted to gently titrate
endogenous inhibition by reducing GABA synthesis
or to enhance excitation by prolonging glutamatergic
synaptic responses (Fig. 2). Both adjustments would
be expected to yield a similar shift of balance in favor
of excitation in vivo.
Distinct genes encode the two isoforms of GABAsynthetic enzyme, glutamic acid decarboxylase
(GAD) (see Soghomonian and Martin, 1998). The
larger 67-kD protein (GAD67) is localized to cell
somata and dendrites, producing a constitutive
concentration of GABA throughout the cell (Fig. 2,
right). In the absence of GAD67, mice die at birth
with brain GABA concentrations less than 10% of
that found in wild-type mice (Asada et al., 1997).
Intriguingly, the 65-kD isoform (GAD65) is found
primarily in the synaptic terminal, where it is
anchored to vesicles and serves as a reservoir of
inactive GAD that can be recruited when additional
GABA synthesis is required (Soghomonian and
Martin, 1998). During intense neuronal activity,
GAD65 may be specialized to respond to rapid
changes in synaptic demand.
Mice carrying a targeted disruption of the GAD65
gene survive and exhibit a normal GABA content in
the adult brain (Asada et al., 1996; Kash et al., 1997).
However, as predicted, they display a significant
reduction of stimulated GABA release (Hensch et al.,
1998; Tian et al., 1999). Due to their activitydependent phenotype, GAD65 knock-out (KO)
mice represent an ideal tool with which to test the
role of endogenous inhibitory circuits in synaptic
plasticity.
To directly affect excitation, we noted the
developmental change in subunit composition of the
N-methyl-D-aspartate (NMDA)-type glutamate
receptor. Composed of a principal subunit NR1
and different modulatory NR2 partners, NMDA
receptor-mediated synaptic current decay is truncated
by an activity-dependent switch in predominant
subunit composition from NR2B to NR2A (Nase et
al., 1999). Indeed, NMDA response kinetics in brain
slices from NR2A knock-out (KO) mouse visual
cortex remain dramatically prolonged well beyond
the critical period, yielding increased charge transfer
through NMDA receptor channels (Fig. 2, left)
(Fagiolini et al., 2003). Global removal of NR1 is
neonatal lethal, whereas conditional NR1 deletion
renders the cortex visually unresponsive (M.F.,
T. Iwasato, S. Itohara, T.K.H., unpublished observations), as observed previously in vivo for pharmacological NMDA receptor antagonists (Miller et al.,
1989). In contrast, NR2A protein expression exhibits
a late postnatal onset in visual cortex (after eyeopening) (Nase et al., 1999; Fagiolini et al., 2003),
making the NR2A KO mouse an ideal candidate to
directly test the role of enhanced excitation conditional to the late postnatal time course of the critical
period.
Indeed, one significant drawback of using firstgeneration KO mice is the potential for compensatory changes and gross developmental defects due to
the chronic deletion of a protein from the entire
animal. To counteract this difficulty of interpretation,
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Fig. 2. Testing the role of excitatory-inhibitory balance in visual cortical plasticity in vivo. Glutamate-mediated excitation is prolonged
(gray traces) through NMDA receptors lacking the NR2A subunit (Fagiolini et al., 2003), yielding increased charge transfer at P28. On
the inhibitory side, GABA is synthesized by two isoforms of the enzyme glutamic acid decarboxylase (GAD). Targeted disruption of
the punctate, synaptic isoform (GAD65) reduces stimulated GABA release from intrinsic interneurons (Hensch et al., 1998; Tian et al.,
1999). Both manipulations would disrupt the balance in favor of excitation, and should be similarly reversed by the use-dependent
GABAA receptor modulator diazepam.
we further attempted to restore the perturbed
excitatory-inhibitory balance in both KO mouse
models by the infusion of benzodiazepine agonists
(Fig. 2). These drugs, such as diazepam, selectively
increase the open probability and channel conductance of a subset of GABAA receptors in a usedependent manner (Cherubini and Conti, 2001), as
they are inert in the absence of synaptic GABA
release. Moreover, benzodiazepine binding sites are
associated with intrinsic cortical elements rather than
thalamocortical axons or other subcortical inputs
(Shaw et al., 1987). Finally, they can be delivered in a
highly restricted manner through the use of osmotic
minipumps for spatial specificity (Fig. 3).
Excitatory-inhibitory balance drives ocular
dominance plasticity
Extracellular single-unit recording from the binocular
zone of visual cortex in GAD65 KO mice reveals
an identical ocular dominance distribution to wildtype animals. The response to a 4-day period of
monocular occlusion beginning between P25 and P27
is, however, strikingly different (Hensch et al., 1998).
Mice lacking GAD65 show no shift in their
responsiveness in favor of the open eye and cortical
neurons continue to respond better to the contralateral eye input (Fig. 3).
In order to rescue the plasticity defect in vivo, we
enhanced inhibition by delivering diazepam (DZ)
locally into one hemisphere during a period of MD
by the use of an osmotic minipump. Drug diffusion is
restricted to the treated visual cortex, while it remains
undetectable in the adjacent temporal cortex, frontal
regions, or opposite hemisphere (Hensch et al., 1998).
Under these conditions, MD now produces a
complete ocular dominance shift in the infused
mutant visual cortex (Fig. 3), whereas no rescue is
observed by administering vehicle solutions or in the
hemisphere opposite to DZ infusion. Consequently,
similar results are obtained with global DZ treatment by intraventricular injections concurrent with
4-day MD.
In adult, nondeprived NR2A KO mice, ocular
dominance distribution is again similar to control
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Fig. 3. Impaired ocular dominance plasticity in GAD65 knock-out (KO) mice is restored by local diazepam infusion. Typical
contralaterally-biased histograms fail to shift toward the open, ipsilateral eye after a brief period of monocular deprivation (MD) due
to reduced GABA release. Osmotic minipump infusion (red area) of the use-dependent GABAA receptor modulator diazepam (DZ)
locally restores inhibitory synaptic transmission and rescues the ocular dominance shift. DZ enhances both the amplitude and decay
kinetics of GABAA receptor-mediated synaptic currents, as they are fully blocked by picrotoxin (PTX). Data adapted from Hensch
et al. (1998).
animals (Fig. 4). Unlike GAD65 KO mice, brief MD
is able to induce a slight shift in favor of the open eye,
but interestingly the overall magnitude of this plasticity is significantly weakened. Long-term MD
(>2 weeks) produces no further shift, confirming
that saturation is reached within four days (Fagiolini
et al., 2003). We then attempted to rescue full
plasticity in NR2A KO mice by DZ infusion
concomitant with brief MD. Similar to GAD65 KO
mice, the ocular dominance distribution shifts
completely with drug treatment (Fig. 4).
A direct physiological consequence of reduced
inhibition in GAD65 KO mice is enhanced activation
in response to visual stimulation (Hensch et al.,
1998). Visual cortical neurons display a tendency
for prolonged discharge as light-bar stimuli exit the
cell’s receptive field (Fig. 5, left), yielding excess
spike firing by single units in all layers that outlasts
the visual stimulus. Correspondingly, NR2A KO
mice also exhibit prolonged neuronal discharge
(76% vs. 2% of cells compared to wild-type)
(Fagiolini et al., 2003), indicating that in both
KO mouse models excitatory-inhibitory balance is
disrupted similarly.
Whereas robust prolonged discharge appears
throughout life in both mutants, it is only evident
early in the life of wild-type animals before the critical
period (Fagiolini and Hensch, 2000), when intrinsic
inhibition is weak, NR2A expression is rising, and
ocular dominance plasticity is absent. Whenever
prolonged discharge is encountered across animals, a
significant reduction (>25% of cells) by DZ infusion
in vivo unmasks visual cortical plasticity (Fig. 5,
right). With the natural appearance of ocular
dominance plasticity during the critical period in
wild-type mice, prolonged discharge drops off
sharply. Further shifting cortical balance in favor of
inhibition with DZ application at this time tends to
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Fig. 4. Impaired ocular dominance plasticity in NR2A knock-out (KO) mice is also rescued by enhancing inhibition with diazepam
(DZ). Typical contralateral bias of normally-reared animals shifts only partially after monocular deprivation (MD) when compared to
wild-type (WT) controls. The CBI only declines fully when MD is combined with DZ injection, but observes the typical critical period
as adult mice do not show plasticity. Data adapted from Fagiolini et al. (2003).
Fig. 5. Prolonged neuronal discharge as a consequence of perturbed excitatory-inhibitory balance in vivo. Neuronal responses exceed
the passage of moving light-bar stimuli beyond the edges of their receptive field. This phenotype is robustly observed in GAD65 and
NR2A KO mice of all ages, but only prior to critical period onset (pCP) in wild-type animals. In all cases, diazepam treatment
significantly reduces the proportion of affected cells to produce full ocular dominance plasticity. Data adapted from Hensch et al.
(1998); Fagiolini and Hensch (2000); Fagiolini et al. (2003).
sharpen plasticity but not significantly beyond the
normal range (Hensch et al., 1998).
Taken together, a delicate equilibrium between
excitation and inhibition intrinsic to visual cortical
circuits is necessary to detect the imbalanced activity
between competing inputs from the two eyes.
Furthermore, fast inhibitory transmission via
GABAA-mediated connections seems to be the main
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driving force in this process, as plasticity impairment
is more potent in the absence of GAD65 than
NR2A and is rescued by benzodiazepines in both
cases.
Mechanisms and future directions
Excitatory-inhibitory balance determines the neural
coding of sensory input. Specific spike timingdependent windows for synaptic plasticity have
recently been elucidated in developing and neocortical structures (Bi and Poo, 2001). Unlike classical
models of LTP induced by changes in mean firing
rate that are strictly blocked by enhancing inhibition
with benzodiazepines (del Cerro et al., 1992; Trepel
and Racine, 2000), spike-timing forms of plasticity
rely upon physiologically realistic, millisecond-scale
changes in the temporal order of pre- and postsynaptic action potentials. Prolonged discharge in
both NR2A and GAD65 KO mice would impair
plasticity by altering the pattern of neural activity
encoding visual input. Diazepam would then subtly
improve temporal processing in both animal models
to fully restore ocular dominance shifts in response to
MD. A competitive outcome is also more readily
understood by spike-timing rather than homosynaptic plasticity rules (Miller, 1996; Song et al., 2000).
Identifying a role for spike timing-dependent
plasticity in vivo must await a molecular component that discriminates it from traditional homosynaptic plasticity induced by high or low-frequency
stimulation.
Tight regulation of neural coding by inhibition
may indeed play the dominant role (Feldman, 2000;
Pouille and Scanziani, 2001). Among the vast
diversity of GABAergic interneurons in neocortex,
two major sub-classes of parvalbumin-containing
cells target the axon initial segment and soma
(DeFelipe, 1997; Somogyi et al., 1998). Both are
ideally situated to control either spike initiation
(chandelier cells) or back-propagation (basket cells),
respectively, required for synaptic plasticity in the
dendritic arbor (Fig. 6). It is possible to reduce the
fast-spiking behavior of these circuits in a cell-type
specific manner by deleting their particular potassium
channels (Kv3.1), and to mimic the global GAD65
KO phenotype (Rudy and McBain, 2001; Matsuda et
al., in revision). Moreover, because distinct GABAA
receptor subunits are enriched at these two discrete
parvalbumin-cell synapses (Klausberger et al., 2002),
their individual contributions to visual cortical
processing and plasticity have now been identified
by point mutations that selectively remove diazepam
sensitivity (Rudolph et al., 2001; Fagiolini et al.,
2004).
Large-basket cells in particular extend a wide,
horizontal axonal arbor that can span ocular
Fig. 6. Specific inhibitory sub-circuits may drive ocular dominance plasticity by regulating spike-timing in the dendrites. Proper
excitatory-inhibitory balance triggers a further cascade of molecular events underlying structural consolidation of developing circuits
leading to critical period closure even in complete darkness.
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dominance columns in cat visual cortex (Buzas et al.,
2001), which are useful in segregating input coming
from the two eyes (Hensch and Strgker, 2004).
Moreover, electrically-coupled networks of fastspiking cells offer a system exquisitely sensitive to
timing that could detect and pass along synchronized
signals (Galaretta and Hestrin, 2001). Coincidence
detection by precise NMDA receptor kinetics instead
does not determine critical period duration, contrary
to traditional LTP-based predictions (Fox, 1995;
Feldman and Knudsen, 1998; Nase et al., 1999).
Plasticity begins and ends normally in the absence of
NR2A (Fagiolini et al., 2003), while parvalbumincells emerge with a postnatal time course that
parallels critical period onset (Del Rio et al., 1994;
Huang et al., 1999).
To reopen ocular dominance plasticity requires a
drastic disruption of extracellular matrix structure.
Recent anatomical evidence has exposed an agedependent, dynamic re-sculpting of dendritic spines
(Grutzendler et al., 2002), GABAergic synapse
formation (Knott et al., 2002) and refinement of
horizontal connections (Trachtenberg and Stryker,
2001) within days of sensory perturbation. Mature
fast-spiking parvalbumin neurons are predominantly
surrounded by perineuronal nets (Hartig et al., 1999),
whose removal by protease treatment reactivates
visual cortical plasticity in adult animals (Pizzorusso
et al., 2002). It will be of interest to determine
how nascent inhibitory connections, while playing
important regulatory roles in refining excitatory
connections, can themselves be consolidated into
the mature circuit.
Excitatory-inhibitory balance thus ultimately
regulates structural consolidation. Systematic mapping of DZ injections to rescue GAD65 KO mice
reveals a minimum requirement of two days at the
beginning of MD (Iwai et al., 2003). Interestingly,
MD induces a peak increase of extracellular
proteolytic activity in visual cortex within two days
(Mataga et al., 2002). This regulation fails to occur in
GAD65 KO mice, suggesting a cascade for plasticity
from functional imbalance to structural change
through the release of factors such as tissue-type
plasminogen activator (tPA). Indeed, the critical
period itself fails to begin in GAD65 KO mice until
DZ infusion (Fagiolini and Hensch, 2000). Just two
days of DZ exposure eventually closes a stereotypical
window (>14 days; see Fig. 1) for plasticity as seen
normally (Iwai et al., 2003). The drug is effective even
in the complete absence of visual input to block the
delay of critical period by dark-rearing in wild-type
animals (Fig. 6). Dark-rearing in fact delays the
development of GABAergic transmission in visual
cortex (Morales et al., 2002), reminiscent of GAD65
deletion.
Thus, proper excitatory-inhibitory balance represents merely the start of the critical period, and much
remains to be elucidated downstream of this trigger
to determine how and why plasticity ends.
Concluding remarks
We have demonstrated the direct control of a
classical critical period plasticity in developing
primary visual cortex by focusing anew on excitatory-inhibitory balance. How general this principle
will be across brain systems remains to be seen. It is
already noteworthy that in the primary motor
nucleus of the zebrafinch (RA), GABA cell number
peaks in striking correlation with the acquisition of
song only in the male birds that sing (Sakaguchi,
1996). In contrast, regions exhibiting persistent
plasticity, such as the olfactory bulb, continue to
generate GABA cells throughout life (Rochefort et
al., 2002). As more becomes known about the
molecular composition and plasticity of inhibitory
synapses, as well as the ultimate structural changes
that hardwire changes, it will become possible to test
the importance of excitatory-inhibitory balance for
critical periods of brain development in ever finer
detail. Unraveling the mechanisms that limit such
dramatic plasticity to early life would pave the way
for novel paradigms or therapeutic agents for
rehabilitation, recovery from injury, or improved
learning across the lifespan.
Acknowledgments
We thank Dr. H. Katagiri for NMDA receptor
physiology, Y. Tsuchimoto for GAD immunostaining; Drs. S. Kash, S. Baekkeskov, K. Obata for
GAD65, and H. Mori, M. Mishina for GluRe1
(NR2A) knock-out animals. Mice were re-derived
and maintained at RIKEN by S. Fujishima and
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Y. Mizuguchi. Supported by RIKEN Brain Science
Institute, CREST, Special Coordination Funds for
Promoting Science and Technology (Japan Science
and Technology Corp.), and Human Frontiers
Science Program (HFSP).
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