Takesian 2013

CHAPTER
Balancing Plasticity/Stability
Across Brain Development
*
Anne E. Takesian*, Takao K. Hensch*,{,1
1
FM Kirby Neurobiology Center, Boston Childrens Hospital, Harvard Medical School,
Boston, MA, USA
{
Center for Brain Science, Department of Molecular & Cellular Biology, Harvard University,
Cambridge, MA, USA
1
Corresponding author: Tel.: 617-384-5882; Fax: 617-495-4038,
e-mail address: hensch@mcb.harvard.edu
Abstract
The potency of the environment to shape brain function changes dramatically across the lifespan.
Neural circuits exhibit profound plasticity during early life and are later stabilized. A focus on the
cellular and molecular bases of these developmental trajectories has begun to unravel mechanisms,
which control the onset and closure of such critical periods. Two important concepts have emerged
from the study of critical periods in the visual cortex: (1) excitatoryinhibitory circuit balance is a
trigger; and (2) molecular brakes limit adult plasticity. The onset of the critical period is deter-
mined by the maturation of specific GABA circuits. Targeting these circuits using pharmacological
or genetic approaches can trigger premature onset or induce a delay. These manipulations are so
powerful that animals of identical chronological age may be at the peak, before, or past their plastic
window. Thus, critical period timing per se is plastic. Conversely, one of the outcomes of normal
development is to stabilize the neural networks initially sculpted by experience. Rather than being
passively lost, the brains intrinsic potential for plasticity is actively dampened. This is demonstrated
by the late expression of brake-like factors, which reversibly limit excessive circuit rewiring beyond
a critical period. Interestingly, many of these plasticity regulators are found in the extracellular mi-
lieu. Understanding why so many regulators exist, how they interact and, ultimately, how to lift them
in noninvasive ways may hold the key to novel therapies and lifelong learning.
Keywords
critical period, GABA, parvalbumin, perineuronal net, lynx1, myelin, epigenetics
1 INTRODUCTION
Neural circuits are shaped by experiencethe potency of which changes dynami-
cally across the lifespan. A focus on the cellular and molecular bases of these changes
Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00001-1
2013 Elsevier B.V. All rights reserved.
3
4 CHAPTER 1 Mechanisms of Critical Period Plasticity
has begun to unravel mechanisms, which control the onset and closure of such crit-
ical periods for plasticity. This work in animal models offers new insight for tapping
into the brains potential to rewire both in the clinic and classroom. Two important
concepts have emerged (Fig. 1A):
(1) Excitatoryinhibitory (EI) circuit balance is a trigger. The classical

enduring loss of visual acuity (amblyopia) due to altered visual input early in life
fails to occur when inhibitory function is compromised (Hensch, 2005). Specific
GABA circuit maturation underlies the onset timing of plasticity and is shifted
across brain regions consistent with the cascading nature of critical periods.
Notably, premature gain of function by pharmacological agents can trigger
premature onset, while genetic disruptions lead to a delay. These manipulations
are so powerful that they can determine whether an animal is before, at the peak,
or past a plastic window. Thus, critical period timing per se is plastic.
(2) Molecular brakes limit adult plasticity. While it is possible that plasticity
factors are simply more abundant early in life, an emerging view is that the brain
FIGURE 1
Mechanisms controlling onset and closure of critical periods. (A) Precocious plasticity is
prevented during the precritical period by early factors, such as polysialic acid (PSA) on
neural cell adhesion molecule (NCAM), limiting PV circuit function. Critical period onset is
triggered once factors such as Otx2, BDNF, and NARP promote PV cell maturation, leading
to an optimal ratio of excitatory and inhibitory circuit activity. This triggers a sequence of
molecular events, including second messenger molecules (CaMKII, ERK), miR-132,
CREB, protein synthesis, protease (tPA) release, and homeostatic factors (TNFa), which
ultimately induce structural changes (spine pruning, regrowth, axonal rewiring). The critical
period then closes as molecular brakes gradually emerge to dampen plasticity, including
PNNs (CSPGs), Nogo receptor (NgR)PirB signaling, Lynx1 and epigenetic changes
(HDAC).
Continued
1 Introduction 5
FIGURE 1Contd
(B) Critical period triggers and brakes act at various sites within cortical microcircuits on
excitatory pyramidal cells (green), PV inhibitory cells (blue), and non-PV inhibitory cells
(gray). Many factors controlling plasticity are found within the extracellular matrix surrounding
PV cells.
is intrinsically plastic, and one of the outcomes of normal development is then to

stabilize the neural networks that are initially sculpted by experience. This is
demonstrated most clearly by the late expression of brake-like factors beyond the
critical period, which act to limit excessive circuit rewiring (Bavelier et al.,
2010). These factors include structural brakes which physically prevent neurite
pruning and outgrowth, and functional brakes acting on neuromodulatory
systems. Their removal unmasks potent plasticity in adulthood, which can be
used to correct neurodevelopmental disorders.
It is increasingly clear that the cortex does not adhere to a simplified model of shift-
ing between plastic and nonplastic states. Instead, transitions in and out of critical
periods might reflect shifts in plasticity sites or mechanisms (Wang et al., 2012)
due to evolving molecular factors or changes in cortical activity patterns
(Toyoizumi et al., 2013). Here, we review recent findings primarily in the visual cor-
tex and discuss how these principles may apply more broadly.
2 CRITICAL PERIODS: PRUNING CIRCUITS

BY EARLY EXPERIENCE
Critical periods have been observed in various systems across species (Hensch, 2004).
Primary sensory areas in particularthe brains first filters to the outside world
exhibit especially striking examples of experience-dependent plasticity during defined
windows of early life. Such periods are needed to establish an optimal neural repre-
sentation of the surrounding environment to guide future action. Given the extraordi-
nary biological resources that must be devoted to rewiring neural circuitry,
concentrating the construction of accurate, immutable maps early in life for use
throughout adulthood may be an efficient strategy. However, this poses limitations
on future revisions to the circuitry. Recent cellular and molecular insights indicate that
biological mechanisms are expressed to ensure that adaptive changes are preferentially
set in place early in life while leaving the door open for lifelong plasticity.
Perhaps the best-studied model of a critical period is the enduring loss of respon-
siveness in primary visual cortex (V1) to an eye deprived of vision. The behavioral
consequence, amblyopia (poor visual acuity), afflicts 25% of the human population
and remains without a known cure in adulthood (Holmes and Clarke, 2006). From the
initial discovery by Hubel and Wiesel 50 years ago, a picture has emerged that inputs
from the two eyes compete with each other when they first converge in V1 onto in-
dividual neurons (Wiesel and Hubel, 1963). With the advent of gene targeting in
mice, it has become possible to directly manipulate the factors which may mediate
such functional and structural rewiring in response to imbalanced sensory
experience.
Binocular interactions are detected by the integrated action of local excitatory
and inhibitory connections in the neocortex. Strikingly, an optimal balance is re-
quired for plasticity to begin. Gene-targeted deletion of the synaptic isoform of
the GABA-synthetic enzyme, GAD65, reduces stimulus-evoked inhibition without
compromising animal survival because normal levels of the GAD67 isoform remain
(Hensch et al., 1998; Tian et al., 1999). In GAD65 knockout (KO) mice, the effects of
monocular deprivation are not observed until inhibitory transmission is restored by
enhancing the postsynaptic sensitivity to GABA with benzodiazepines (Fagiolini and
Hensch, 2000; Hensch et al., 1998). Agonists, such as diazepam (valium) or zolpi-
dem (ambien), increase the chloride flux through particular GABAA channels when
they are bound together with endogenous transmitter (Cherubini and Conti, 2001),
effectively compensating for poor presynaptic GABA release.
Both GAD65 KO mice (at any age) as well as immature wild-type animals just
after eye opening (around postnatal day P12 in mice) exhibit weak GABA release
and no loss of visual responsiveness to an eye deprived of vision. However, plasticity
can be rapidly switched on by just 2 days of local diazepam infusion into V1 (Iwai
et al., 2003). This represents the first direct control over critical period timing in any
system, and is surprisingly dictated by the late maturation of inhibitory function. Un-
less a favorable EI balance is achieved, plastic changes are not engaged. Recently,
2 Critical Periods: Pruning Circuits by Early Experience 7
this principle has been extended to the cerebellum, where elimination of excessive
climbing fiber inputs onto Purkinje cells during an early critical period is regulated
by GABA levels (Nakayama et al., 2012).
Downstream of the EI trigger, lies a sequence of structural changes which ulti-
mately execute circuit rewiring and its consolidation (Hensch, 2005). Regulated re-
lease of proteases such as tissue-type plasminogen activator (tPA) cleaves the
physical connections between pre- and postsynaptic partners to induce dendritic
spine motility (Mataga et al., 2004; Oray et al., 2004). This requires 2 days of mon-
ocular deprivation once GABA function is mature, and persists for about 1 week.
During this time, spines are lost and then gradually recover as tPA levels return
to baseline (Mataga et al., 2002, 2004).
Finally, the classical shrinkage of deprived eye axons and later sprouting of open
eye axons from the visual thalamus (LGN) is observed, requiring new protein syn-
thesis (Antonini and Stryker, 1993; Antonini et al., 1999; Taha and Stryker, 2002;
Trachtenberg and Stryker, 2001). Several factors have further been identified to cou-
ple EI circuit balance to the physical rewiring process, such as protein kinases
(CaMKII, PKA, ERK; Di Cristo et al., 2001; Fischer et al., 2004; Taha et al.,
2002; Yang et al., 2005) and homeostatic regulators which ultimately strengthen
open eye connections (TNFa; Kaneko et al., 2008a).
Recently, an experience-dependent MicroRNA (miRNA), miR-132, has been
identified in mouse V1 that is important for ocular dominance plasticity. miRNAs
are small non-coding RNAs that regulate post-transcriptional gene expression.
Visual experience induces histone mark modifications at CRE loci close to the
miR-132 coding sequence (Tognini et al., 2011). Such modifications may underlie
the developmental upregulation of miR-132 that occurs after eye opening and per-
sists throughout the critical period. Manipulating miR-132 in vivo, by either increas-
ing levels with a double-stranded mimic (Tognini et al., 2011) or decreasing them
with a competitive inhibitor (sponge)-expressing lentivirus that sequesters endoge-
nous miR-132 (Mellios et al., 2011), completely blocks ocular dominance plasticity
during the critical period. miR-132 elevates the percentage of mushroom/stubby
spines, suggesting that it may play a role in the structural modifications that occur
during critical periods.
Notably, neither the release of tPA, pruning of spines, nor the rewiring of thala-
mocortical afferents occurs readily in adulthood. Rather than a simple loss of plas-
ticity machinery, recent evidence detailed below reveals that further rewiring is
actively gated in the mature brain. This notion of molecular brakes on plasticity
is already evident during the critical period. Spine maturation is normally slowed
down by cell adhesion molecules like Icam-5 (aka telencephalin; Matsuno et al.,
2006). Genetic deletion of Icam-5 accelerates tonotopic map changes in primary au-
ditory cortex (A1), effectively shortening the duration of the critical period (Barkat
et al., 2011). Windows of plasticity, therefore, arise between the maturation of an
optimal EI balance controlling the machinery of synaptic pruning and a later set
of emerging brake-like factors, which persistently offset them (Fig. 1A).
3 CRITICAL PERIOD PLASTICITY OF EXCITATORY

AND INHIBITORY CIRCUITS
The precise response to developmental experience reflects dynamic excitatory and
inhibitory circuits displaying transient changes following sensory manipulation
(Feldman, 2009; Hooks and Chen, 2007; Levelt and Hubener, 2012). Studying these
dynamics has provided new insight into both the induction and expression of critical
period plasticity (Fig. 1B).
3.1 Excitatory Circuit Plasticity During Critical Periods

Thalamocortical synapses are appealing sites for experience-dependent plasticity, as
various studies reveal changes at these synapses that are restricted to developmental
critical periods. This concept originated from early work using thalamocortical brain
slices which preserve the thalamus, cortex, and the connections between them. For
example, in somatosensory cortex, stimulation of the thalamic afferents paired with
postsynaptic depolarization of layer (L)4 cells readily induces long-term potentiation
(LTP; Crair and Malenka, 1995) and long-term depression (LTD; Feldman et al.,
1998). However, this plasticity is diminished in older animals.
Age-restricted thalamocortical synapse plasticity has also been shown in visual
(Jiang et al., 2007) and auditory cortices (Barkat et al., 2011; Chun et al., 2013). Fur-
ther support for this site of plasticity comes from a recent study evaluating the effects
of early deprivation in monocular V1 using optogenetic stimulation of the thalamic
afferents. Three days of monocular deprivation during the critical period induces a
specific depression of thalamic inputs to L4, but leaves thalamic inputs to L6 and
cortico-cortical connections unaltered (Wang et al., 2013).
Until recently, the consensus has been that such thalamocortical plasticity is lost
in the adult. However, it was recently discovered that thalamocortical LTP and LTD
are present in animals aged far beyond critical periods and gated by modulatory sys-
tems. These include cholinergic activation of muscarinic receptors, consistent with
the role of these receptors in inducing adult in vivo tonotopic map plasticity
(Blundon and Zakharenko, 2013; Blundon et al., 2011; Chun et al., 2013). Several
studies now point to thalamocortical inputs as important loci for adult plasticity.
For example, peripheral nerve injury induced in rats aged beyond the critical period
strengthens thalamocortical connections to L4 cells in the spared rat barrel cortex (Yu
et al., 2012).
Changes within intracortical excitatory circuits are also associated with critical
periods. Whisker deprivation leads to intracortical suppression of cortical L2/3
(Drew and Feldman, 2009) by weakening L4 to L2/3 synapses (Bender et al.,
2006). Such synaptic depression only occurs after a developmental shift in the spike
timing-dependent plasticity (STDP) rule at L4-L2/3 synapses toward the end of the
second postnatal week (Itami and Kimura, 2012). Similarly, potentiation of
responses to spared whiskers is induced at L4 to L2/3 synapses (Clem and Barth,
2006) during a critical period, also occurring at the end of the second postnatal week
3 Critical Period Plasticity of Excitatory and Inhibitory Circuits 9
(Wen and Barth, 2011). Effects of deprivation within intracortical circuits have also
been shown to be age dependent in V1 by examining excitatory connections between
L4 pyramidal cells using paired recordings. Whereas deprivation during the precrit-
ical period increases the strength of these connections, the same manipulation during
the critical period leaves these synapses unaltered (Maffei et al., 2004, 2006). Such
age-dependent changes within these V1 intracortical networks may be due to devel-
opmentally-gated plasticity mechanisms. During the precritical period, LTD is read-
ily induced; however, upon critical period opening, LTD induction fails and is
replaced by LTP. This developmental switch in the sign of plasticity is prevented
by visual deprivation, suggesting that the recruitment of critical period plasticity
mechanisms is triggered by experience (Wang et al., 2012). In contrast, intracortical
excitatory plasticity within auditory cortex shows similar plasticity expression and
mechanisms throughout life (Blundon and Zakharenko, 2013).
In addition to synaptic changes, critical period plasticity may involve alterations
in intrinsic cell excitability. High-frequency firing in cortical pyramidal cells leads to
a long-lasting increase in evoked firing rates. This increased excitability depends
upon the recruitment of a signaling cascade involving PKA and calcium
(Cudmore and Turrigiano, 2004) that reduces a persistent potassium current
(IK-TEA; Nataraj et al., 2010). It has recently been suggested that such intrinsic plas-
ticity may play a role in critical periods. Cells acquire this form of plasticity at a post-
natal age that coincides with the critical period onset. However, monocular
deprivation during the critical period reduces cell excitability and increases IK-TEA
in monocular V1 (where competition from the other eye is not possible), presumably
by preventing this form of plasticity (Nataraj et al., 2010). Notably, monocular and
binocular visual cortices show distinct temporal profiles of intrinsic plasticity
expression and differential effects of deprivation (Nataraj and Turrigiano, 2011).
Immediate electrophysiological changes are followed by structural changes in
excitatory synapses and axonal projections. Across brain regions, spines are more
dynamic during early life than in adults (Alvarez and Sabatini, 2007). For example,
pruning of spines along pyramidal cell dendrites occurs in binocular V1 following
monocular deprivation during the critical period, but fails to be seen in adulthood
(Mataga et al., 2004; Oray et al., 2004). Parallel changes in thalamic axons are in-
duced by monocular deprivation, causing shrinkage of arbors arising from the closed
eye and expansion of arbors serving the open eye (Antonini and Stryker, 1993, 1996).
Structural changes may also occur in A1 during critical periods. The tonotopic crit-
ical period is associated with a rapid maturation of stubby spines (Barkat et al., 2011),
which are direct targets of thalamocortical axons (Richardson et al., 2009).
3.2 Inhibitory Circuit Plasticity During Critical Periods

There is accumulating evidence that experience-dependent changes within inhibitory
circuits also play a key role in critical periods (Aton et al., 2013; Gandhi et al., 2008;
Kameyama et al, 2010; Kuhlman et al., 2013; Yazaki-Sugiyama et al., 2009). With
the vast majority of past studies focused on excitatory synapse plasticity onto
principal cells, less attention was directed toward plasticity of inhibition. However, a
barrage of recent studies has made it clear that both GABAergic synapses and
glutamatergic synapses onto inhibitory neurons exhibit robust activity-dependent
plasticity (Kullmann et al., 2012).
Across brain regions, developing inhibitory cells are susceptible to early life sen-
sory experience (Feldman, 2009; Hensch, 2005; Le Magueresse and Monyer, 2013;
Sanes and Kotak, 2011; Takesian et al., 2009). Partial or total loss of activity in sen-
sory cortex generally leads to downregulation of GABAergic transmission. Blocking
activity with tetrodotoxin leads to a decline in miniature inhibitory current ampli-
tudes in visual cortical cultures (Kilman et al., 2002). This is consistent with the ef-
fects of sensory deprivation: dark rearing from birth (Morales et al., 2002), whisker
trimming during a critical period (Jiao et al., 2006), and early hearing loss (Kotak
et al., 2008; Takesian et al., 2010) all reduce the amplitude of inhibitory currents
recorded in cortical excitatory cells.
Such inhibitory plasticity may be developmentally regulated. Deprivation before
or after the critical period does not cause the same readjustments in inhibitory func-
tion (Maffei et al., 2010; Morales et al., 2002; Takesian et al., 2012; Yazaki-
Sugiyama et al., 2009). Experience-dependent changes of inhibitory function are
consistent with anatomical alterations in the number of inhibitory synapses. For ex-
ample, in A1, developmental hearing loss leads to a significant reduction in the num-
ber of inhibitory terminals identified by GAD immunoreactivity (Sarro et al., 2008).
In somatosensory cortex, neonatal whisker trimming reduces inhibitory synapses by
52% (Sadaka et al., 2003). Early visual deprivation leads to a decline in the inhibitory
innervation of cortical pyramidal cell somata (Chattopadhyaya et al., 2004; Kreczko
et al., 2009). Thus, sensory experience has an impact on the establishment of cortical
inhibitory projections across brain regions.
Cortical inhibitory synapses are formed by a diverse group of GABAergic inter-
neurons (Markram et al., 2004) that respond differentially to early sensory experi-
ence. Early monocular deprivation induces a robust decrease in the strength of
inhibitory connections between fast-spiking, parvalbumin (PV)-expressing cells
and pyramidal cells; however, inhibitory connections formed by regular-spiking
nonpyramidal interneurons exhibit an opposite increase in strength (Maffei et al.,
2004). Similarly, dark rearing reduces the response evoked by laser photo-uncaging
of GABA onto somatic but not axonal receptors (Katagiri et al., 2007).
Early auditory deprivation also induces cell type-specific adjustments of cortical
inhibitory pathways. The PV cell pathway exhibits both a reduction of fast excitatory
drive onto PV neurons and a reduction of inhibitory drive from PV to pyramidal neu-
rons; whereas, the low-threshold spiking inhibitory pathway does not (Takesian
et al., 2010, 2013). The divergent effects of sensory experience on inhibitory cell
subtypes suggest that these cells may play diverse roles in critical period plasticity
(see Section 4).
Single-cell recordings in vivo reveal that PV cells in V1 undergo bidirectional
plasticity in response to monocular deprivation: an early paradoxical shift toward
the closed eye inputs after 3 days of deprivation and then a later shift toward the open
4 Critical Period Triggers and Brakes 11
eye inputs (Yazaki-Sugiyama et al., 2009). This change in bias can be explained by
applying STDP rules and offers a novel mechanism for the suppression of deprived
eye responses during the early phase of ocular dominance plasticity. Recently, even
faster dynamics have confirmed decreased PV cell firing rates already 1 day after
deprivation when excitatory cells remain unaffected (Kuhlman et al., 2013). The
degree to which PV cells are suppressed within hours after closing one eye of kittens
predicts the degree to which neighboring excitatory cells will undergo ocular
dominance plasticity (Aton et al., 2013).
A similar reduction of thalamocortical drive onto PV cells occurs in the somato-
sensory (Chittajallu and Isaac, 2010) and auditory cortices (Takesian et al., 2013)
following sensory deprivation, yielding decreased feed-forward inhibition onto ex-
citatory cells (Chittajallu and Isaac, 2010). Notably, a rapid reduction of inhibition in
response to nucleus basalis (NB)-tone pairing in mature A1 may be necessary for
adult receptive field plasticity (Froemke et al., 2007). In adult V1, recent evidence
suggests a structural loss of inhibitory synapses onto pyramidal neurons is an effec-
tive component of experience-induced plasticity with limited need for rearranging
the excitatory circuitry (Chen et al., 2011; van Versendaal et al., 2012). These studies
highlight the importance of understanding the transient sensory-evoked changes in
inhibition, which may be a fundamental mechanism of cortical plasticity.
4 CRITICAL PERIOD TRIGGERS AND BRAKES

4.1 Inhibitory Control of Plasticity
Directly manipulating inhibitory transmission leads to shifts in the timing of the crit-
ical period for ocular dominance plasticity (Hensch, 2005). Critical period onset is
accelerated by activating GABAA inhibitory receptors prematurely with benzodiaz-
epines (Fagiolini and Hensch, 2000; Fagiolini et al., 2003; Hensch et al., 1998; Iwai
et al., 2003), or by promoting inhibitory circuit maturation (Di Cristo et al., 2007;
Hanover et al., 1999; Huang et al., 1999; Sugiyama et al., 2008). Instead, critical
periods are delayed into adulthood by KO or knockdown of the GABA synthesizing
enzymes, GAD65 (Fagiolini and Hensch, 2000; Hensch et al., 1998) and GAD67
(Chattopadhyaya et al., 2007).
Plasticity is conversely reopened after the critical period by reducing inhibition to
immature levels. Intracortical microperfusion of the GAD inhibitor, MPA, or the
GABAA receptor antagonist, PTX, promotes ocular dominance plasticity in adult
V1 (Harauzov et al., 2010). Remarkably, transplantation of immature inhibitory neu-
rons into the postnatal visual cortex promotes ocular dominance plasticity even after
the natural critical period (Southwell et al., 2010). Embryonic precursors of inhibi-
tory cells from the medial ganglionic eminence transplanted into the brains of mice
shortly after birth eventually integrate into the visual cortical circuits. Notably, this
induces ocular dominance plasticity only once the transplant reaches a cellular age
(1 month old) similar to that of endogenous inhibitory cells during the typical
critical period.
Only a1-containing GABAA receptors, which are preferentially expressed and

targeted by large basket PV cells, drive visual cortical plasticity (Fagiolini et al.,
2004). During development, the strength of these PV-to-pyramidal cell inputs
increases in an experience-dependent manner, reaching an optimal threshold to
promote large-scale cortical plasticity (Katagiri et al., 2007). As detailed later, the
maturational state of PV cells interestingly requires interactions with its surrounding
extracellular milieu (Fig. 1B). Thus, plasticity onset is triggered by non-cell auton-
omous factors which promote PV cell maturation, such as brain-derived neurotrophic
factor (BDNF) and orthodenticle homeobox 2 (Otx2; Sugiyama et al., 2008).
The extracellular environment may in fact prevent premature Otx2 transfer and
precocious plasticity during the precritical period. For example, polysialic acid
(PSA) attaches to neural cell adhesion molecule and entraps homeodomain proteins
(Joliot et al., 1991). PSA expression in mouse V1 declines shortly after eye opening.
Premature PSA removal promotes maturation of perisomatic GABAergic innerva-
tion and triggers a precocious critical period for ocular dominance plasticity
(Di Cristo et al., 2007). Conversely, molecular brakes such as perineuronal nets
(PNNs) and Lynx1 emerge with critical period closure to modulate PV cell function
(Beurdeley et al., 2012; Morishita et al., 2010), as discussed below.
4.2 Brain-derived neurotrophic factor

Genetic enhancement of BDNF, in particular, triggers an early ocular dominance
critical period by promoting inhibitory circuit maturation in V1 (Hanover et al.,
1999; Huang et al., 1999). Precocious BDNF expression accelerates visual acuity
(Huang et al., 1999), whereas blockade of BDNF signaling prevents the development
of ocular dominance columns in kitten V1 (Cabelli et al., 1997). Instead, TrkB
receptor kinase activity is not required for any of the plastic effects of deprivation
itself (Kaneko et al., 2008b). Other neurotrophins may act differently on visual sys-
tem development and plasticity (Lodovichi et al., 2000).
BDNF transcription, trafficking, and secretion are dynamically modulated in an
activity-dependent manner (Greenberg et al., 2009). Cortical BDNF is kept at imma-
ture levels by manipulations which delay critical periods, including dark rearing
(Castren et al., 1992) and acoustic white noise exposure (Zhou et al., 2011).
Recently, it has been found that infusion of BDNF in auditory cortex amplifies tono-
topic map plasticity in response to pure tone exposure during the critical period
(Anomal et al., 2013). Conversely, BDNF blockade leads to distorted tonotopic or-
ganization and reduced spectral tuning. These effects were associated with changes
in GABA receptors. Thus, BDNF may control critical period timing across regions
by the activity-dependent modulation of PV cell maturational state.
4.3 Extracellular Matrix: PNNs and Otx2

PNNs, composed of chrondroitin sulfate proteoglycans (CSPGs) and other extracel-
lular matrix components, have been found to play an important role in plasticity by
modulating PV cell function (Berardi et al., 2004; Galtrey and Fawcett, 2006). These
lattice-like structures surround cell bodies and proximal neurites, preferentially

ensheathing mature PV cells (Hartig et al., 1999). The progressive developmental
increase in PNNs is thought to contribute to the closure of critical periods across di-
verse brain regions. In the visual system, PNN expression increases across postnatal
development, coincident with closure of the critical period for ocular dominance
plasticity (Pizzorusso et al., 2002; Sur et al., 1988).
PNNs similarly appear at the closure of the critical period in the mouse barrel
cortex (McRae et al., 2007). Within nucleus HVC of the zebra finch brain, the per-
centage of PV-expressing neurons with PNNs dramatically increases during song
learning and predicts song maturity (as measured by temporal variance; Balmer
et al., 2009). Finally, the emergence of PNNs in the developing amygdala is associ-
ated with the closure of a critical period for fear extinction. Whereas young mouse
pups can permanently erase an acquired fear memory by extinction training, adult
animals exhibit persistent fear behaviors that are resistant to erasure. The age at
which this developmental switch in fear memory resiliency occurs is coincident with
a sharp increase in PNN expression in the basolateral amygdala (Gogolla et al.,
2009a).
PNN expression is decreased by manipulations that delay the closure of critical
periods, such as visual deprivation in developing cats and mice (Sur et al., 1988; Ye
and Miao, 2013), whisker trimming in developing mice (McRae et al., 2007), or
acoustic isolation of developing zebra finches (Balmer et al., 2009). PNN expression
is instead not affected by adult sensory deprivation (McRae et al., 2007; Sur et al.,
1988), suggesting that there is a critical period for normal PNN development. Strong
evidence for a role of PNNs in regulating plasticity comes from studies reporting
reactivation of critical periods by degradation of PNNs. Their degradation by
chondroitinase-ABC in adult V1 reopens sensitivity to monocular deprivation and
restores visual acuity to amblyopic rats (Pizzorusso et al., 2002, 2006). Similarly,
in the adult basolateral amygdala, PNN degradation reopens a critical period during
which fear memories are once again fully erased by extinction training (Gogolla
et al., 2009a).
PNNs may limit PV cell plasticity by controlling the concentration of extracel-
lular ions that surround these cells or by sequestering molecular factors which
regulate plasticity (Hartig et al., 1999; Hensch, 2005; Sugiyama et al., 2008,
2009). For instance, PNNs permit the capture of the Otx2 homeoprotein by PV
cells. After eye opening, Otx2 is translocated into visual cortex in an activity-
dependent manner from the retina (Sugiyama et al., 2008). More recently, the cho-
roid plexus has been identified as an additional source (Spatazza et al., 2013).
The accumulation of Otx2 within PV cells accelerates and maintains their matura-
tion, elevating markers of fast-spiking PV cell function (PV, K3.1b potassium chan-
nels, GAD65, and GABAA a1 receptor subunit) and triggering plasticity onset
(Sugiyama et al., 2008).
PNNs and Otx2 colocalize in the adult visual cortex (Beurdeley et al., 2012;
Sugiyama et al., 2008), and PNN degradation leads to an 80% reduction in the num-
ber of Otx2-positive cells (Beurdeley et al., 2012). A classical glycosaminoglycan-
binding motif (RK doublet) has been identified within Otx2 that recognizes CSPGs
and mediates Otx2 binding to PNNs. Infusing an RK peptide to block this specific
recognition significantly decreases Otx2 content of PV cells (Beurdeley et al., 2012).
Strikingly, this blockade of Otx2 transfer within cortex (Beurdeley et al., 2012) or
knockdown of Otx2 synthesis from the choroid plexus (Spatazza et al., 2013) reac-
tivates ocular dominance plasticity in mature V1, enabling recovery from amblyopia.
The CSPG sulfation patterns determine the condensation of CSPGs into tight
PNNs. Developmental increases in the carbon 4-/6-sulfation ratio of CSPGs occur
in parallel with critical period closure. This shift occurs in the somatosensory cortex
before the visual cortex, consistent with the staggered windows of plasticity between
these regions. Transgenic mice engineered to retain a low 4S/6S ratio exhibit deficits
in normal PNN formation and disrupted Otx2 transfer into PV cells (Miyata et al.,
2012). These mice, as well as those lacking the link protein that forms the PNN back-
bone (Carulli et al., 2010), then show extended plasticity into adulthood.
Together, these studies suggest that PNNs play a persistent role in controlling
plasticity by capturing Otx2 within PV cells. Otx2 regulation of plasticity can be
explained by a two-threshold model: the critical period is triggered as Otx2 is first
captured by PV cells, but then closes as maturing PNNs condense and permit even
higher levels of Otx2 to accumulate. Otx2 protein is present in PV cells across var-
ious brain regions outside of the visual cortex, including prefrontal, auditory, and
somatosensory cortices, as well as the basolateral amygdala and hippocampus, sug-
gesting that this factor may be a global regulator of PV cell maturation and associated
critical period plasticity (Spatazza et al., 2013).
4.4 Narp
In addition to Otx2, PNNs might also facilitate the accumulation of other molecules
that modulate PV cell function. For example, the build-up of neuronal activity-
regulated pentraxin (NARP) at excitatory synapses onto PV cells depends upon
the presence of PNNs. Narp is an activity-dependent protein that is secreted from
presynaptic excitatory neurons and regulates GluR4-containing AMPA receptor
levels in hippocampal PV cells. Genetic deletion of Narp prevents homeostatic upre-
gulation of excitatory input onto these PV cells during increased network activity
(Chang et al., 2010). In V1, Narp KO mice show reduced excitatory drive onto
PV cells, resulting in widespread hyperexcitability that is reminiscent of the imma-
ture cortex. Strikingly, these mice fail to express ocular dominance plasticity
throughout life, suggesting that Narp-dependent enhancement of excitatory drive
onto PV cells plays an important role in opening critical periods (Gu et al., 2013).
4.5 Myelin and Myelin-Associated Inhibitors

Emerging studies now implicate myelin and myelin-associated inhibitors in control-
ling critical periods. Proteins found in myelin, including Nogo-A/B, myelin-associated
glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein, limit axonal sprout-
ing upon binding to the Nogo receptor (NgR) and paired immunoglobulin-like receptor
B complex (PirB; Atwal et al., 2008). Adult mice lacking NgR or its ligands (Nogo-
A/B) exhibit ocular dominance plasticity well beyond the critical period (McGee et al.,
2005), as do mice lacking functional PirB, revealed by a greater cortical induction
of the activity-regulated immediate-early-gene Arc upon open eye stimulation
(Syken et al., 2006).
NgR deletion also reopens a critical period for acoustic preference in mice. Ex-
posing WT juvenile mice to music reverses their innate preference to dwell in a silent
shelter. However, WT mice exposed as adults continue to show a preference for si-
lence, suggesting that acoustic preference is shaped during an early critical period.
However, mice lacking the gene for NgR maintain an open-ended critical period,
continuing to show shifts in acoustic preference into adulthood. This shift in prefer-
ence is associated with elevated activation of the medial prefrontal cortex, as
assessed by cFos expression (Yang et al., 2012). Therefore, NgRs may limit plastic-
ity within diverse circuits beyond primary sensory regions.
Limiting structural changes may be one mode of NgR action. Two photon in vivo
imaging in somatosensory cortex reveals increased dendritic spine turnover in adult
mice lacking NgR1, similar to levels observed in juvenile mice (Akbik et al., 2013).
These mutants also exhibit more robust extinction of freezing following fear condi-
tioning (Akbik et al., 2013), a behavior that is associated with spine turnover (Lai
et al., 2012). Interestingly, NgR is also expressed in PNN-ensheathed (presumably
PV) cells in mouse V1 (Ye and Miao, 2013) and has been found to act as a receptor
for CSPGs (Dickendesher et al, 2012). Dark rearing from birth prevents the dramatic
developmental increase in NgR within PNN-bearing cells. Thus, a potential cross-
talk between myelin factors and PNNs might stabilize synapses in adulthood,
restricting spine turnover on pyramidal cells as well as input onto aspiny PV cells.
Proper development of myelin depends upon the early environment. Social experi-
ence may regulate myelination in the prefrontal cortex during a developmental critical
period. Mouse pups socially isolated for 2 weeks after weaning showed deficits in PFC-
dependent behaviors, such as sociability and working memory. These deficits were ac-
companied by alterations in oligodendrocyte morphology and a reduced expression of
myelin genes, like MAG and myelin basic protein (Makinodan et al., 2012). A specific
ErbB3 signaling pathway is essential for this experience-dependent maturation of
oligodendrocytes and behavior (Makinodan et al., 2012). Notably, these changes occur
in a juvenile critical period overlapping that of acoustic preference behaviors in PFC
(Yang et al., 2012) and are not reversed by subsequent exposure to a social environment.
Thus, changes in myelin signaling may impact a range of critical periods, shaping di-
verse neural processes from basic sensory perception to higher order cognition.
4.6 Epigenetic Regulation

Accumulating evidence suggests that brain circuits respond to environmental signals
via dynamic changes in DNA methylation and histone modifications (Fagiolini et al.,
2009). DNA methylation is the conversion of cytosine to 5-methylcytosine in CpG
dinucleotides. The process depends upon the presence of methyl donors and is
catalyzed by DNA methyltransferases. DNA methylation represses transcription

directly by interfering with the binding of transcription factors or indirectly by
recruiting repressor complexes containing histone deacetylases (HDACs) to con-
dense chromatin structure (Burgers et al., 2002; Klose and Bird, 2006).
Dynamic changes in methylation of both the glucocorticoid receptor (Zhang and
Meaney, 2010), and more recently its regulatory target FKBP5 (Klengel et al., 2013),
in response to early life stress or degree of maternal care have been well documented.
Developmental changes in such posttranslational modifications may underlie critical
period transitions. Closure of the critical period for ocular dominance is associated
with a downregulation of visual experience-induced histone acetylation and phos-
phorylation. Trichostatin A, valproate or sodium butyrate, HDAC inhibitors which
increase histone acetylation, reactivate ocular dominance plasticity after the critical
period (Putignano et al., 2007) and enable recovery from amblyopia in adulthood
(Silingardi et al., 2010). Valproate also reopens critical-period learning of absolute
pitch in humans (Gervain et al., 2013).
Epigenetic factors regulate GAD67 (Huang and Akbarian, 2007), reelin, an ex-
tracellular matrix protein preferentially secreted by GABAergic neurons (Levenson
et al., 2008; Lewis et al., 2005), and BDNF (Martinowich et al., 2003). In addition,
oligodendrocytes are known to be epigenetically dynamic (Shen et al., 2008), and
valproate treatment reopens critical periods for acoustic preference in the PFC, mim-
icking NgR deletion (Yang et al., 2012). It will be essential to determine how global
epigenetic alterations induced by HDAC inhibitors or early life stress impact the
brain in a cell-specific manner.
5 CRITICAL PERIOD GATING

5.1 How do PV Circuits Control Plasticity?
Although it is clear that PV cells are a central hub controlling critical period timing,
the way in which these cells regulate plasticity remains elusive. Recent studies have
proposed that a transient suppression of PV cells may gate cortical plasticity. For
example, excitatory drive onto PV cells is reduced by 70% as rapidly as 1 day after
monocular deprivation during the critical period (Aton et al., 2013; Kuhlman et al.,
2013; Yazaki-Sugiyama et al., 2009). Mimicking a transient 24 h reduction of inhi-
bition upon eyelid suture by selective activation of DREADD receptors within PV
cells enables plasticity beyond the critical period (Kuhlman et al., 2013).
First, it is possible that the strong perisomatic inhibition that PV cells generate in
pyramidal cells alters synaptic plasticity rules. GABA receptor antagonists increase
the probability of inducing LTP by tetanic stimulation to the white matter in rat vi-
sual cortical slices even beyond the critical period (Harauzov et al., 2010; Kirkwood
and Bear, 1994). Fast, disynaptic inhibition generated by PV cells restricts the tem-
poral window during which postsynaptic inputs can summate and potentiate by
STDP. Robust perisomatic control of back-propagating action potentials in particular
5 Critical Period Gating 17
may favor temporally coherent inputs for STDP, enhancing synaptic competition
(Hensch, 2005; Kuhlman et al., 2010).
A role for GABA in synaptic competition is elegantly demonstrated in a recent
study using two-color uncaging of glutamate and GABA onto rat hippocampal CA1
pyramidal cells. GABA uncaging induces spine shrinkage and elimination when
paired with a STDP protocol, which depends upon a signaling cascade involving
NMDA receptors, calcineurin, and actin depolymerizing factor (Hayama et al.,
2013). To examine heterosynaptic competition along a dendrite, neighboring spines
were stimulated: one spine with an LTP protocol to induce enlargement and a neigh-
boring spine with an LTD protocol to induce shrinkage. Remarkably, GABA induces
widespread spine shrinkage across the dendrite to neighboring spines, except for the
spine stimulated with the LTP protocol (Hayama et al., 2013). In this manner, GABA
promotes the competitive selection of individual spines along a dendrite, a process
that is elevated during critical periods of development (Hensch, 2005).
A second possible mechanism is that PV circuits may initiate a cascade of mo-
lecular events that create a permissive extracellular milieu for structural changes. For
example, altered inhibition may trigger a transient increase in proteolytic activity by
the tPA enzyme that degrades the extracellular matrix. tPA elevation during monoc-
ular deprivation underlies the spine pruning that is essential for ocular dominance
plasticity (Mataga et al., 2002, 2004; Oray et al., 2004). This deprivation-induced
increase in tPA, along with spine pruning, fails to occur in mature mice or those lack-
ing GAD65 (Mataga et al., 2002, 2004).
A third mechanism may involve the coordination of synchronized network activ-
ity. PV cells form networks that are interconnected by both chemical and electrical
synapses (Galarreta and Hestrin, 2002). Such networks show synchronous activity
and play an important role in generating gamma (30100 Hz) rhythms in the cortex
and hippocampus (Cardin et al., 2009; Fuchs et al., 2007; Le Magueresse and Monyer,
2013; Sohal et al., 2009). During early postnatal life, emergence of the mature elec-
trophysiological properties of PV cells may lead to more coherent network activity of
higher gamma band frequencies (Doischer et al., 2008). It is currently unknown
whether such coordinated activity contributes to critical period plasticity.
A fourth theory is that inhibitory maturation enables the transition from precrit-
ical period to critical period plasticity by reducing spontaneous activity. This hypoth-
esis takes note of the fact that many forms of activity-dependent plasticity are equally
robust before and during the critical period. Therefore, critical period onset may not
reflect the engagement of new plasticity mechanisms, but rather when there is a shift
in the predominant learning cues from internally driven spontaneous activity to ex-
ternally driven sensory-evoked activity (Toyoizumi et al., 2013). Recordings from
awake-behaving mice confirm that critical period onset is accompanied by a reduc-
tion in the spontaneous-to-visual activity ratio. Therefore, shifts in spontaneous-to-
evoked ratios may be timed to match distinct critical periods across cortical regions,
representing a global mechanism governing developmental plasticity.
Finally, it is possible that inhibitory circuit plasticity itself underlies the changes
in cortical response properties that occur during critical periods (Aton et al., 2013;
Gandhi et al., 2008; Kameyama et al, 2010; Kuhlman et al., 2013; Ma et al., 2013;
Yazaki-Sugiyama et al., 2009). By understanding how experience-dependent alter-
ations of the PV circuit influence cortical plasticity, we will gain insight into the con-
ditions that make the circuits of the brain most labile to experience.
5.2 Modulation of PV Circuits

Various endogenous mechanisms, including modulators and extracellular factors,
may act to downregulate PV cell function to gate plasticity. First, specific disinhi-
bitory circuits, in which PV cells are suppressed by other GABAergic interneurons,
might contribute (Fig. 1B). Across cortices, it has been shown that PV cells are
highly interconnected, strongly inhibiting one another (Avermann et al., 2012;
Galarreta and Hestrin, 2002; Galarreta et al., 2008; Gibson et al., 1999; Pfeffer
et al., 2013). Furthermore, somatostatin-expressing inhibitory cells in somatosensory
(Xu et al., 2013) and visual cortices (Pfeffer et al., 2013) preferentially target PV
cells, reducing PV cell spiking and thus increasing the firing of neighboring pyrami-
dal neurons (Xu et al., 2013). Interneurons within the superficial cortical layers,
which are activated by modulators (Arroyo et al., 2012; Lee et al., 2010; Letzkus
et al., 2011) and by projections from matrix thalamic nuclei (Cruikshank et al.,
2012), also generate inhibition within PV cells (Arroyo et al., 2012; Letzkus
et al., 2011). This L1 cell-mediated disinhibitory circuit in auditory cortex is required
for fear learning (Letzkus et al., 2011). It will be important to determine whether
these disinhibitory circuits also gate plasticity during developmental critical periods.
Second, neuromodulators, such as acetylcholine or serotonin, may be critically
involved in plasticity through their impact on PV cell function. The cholinergic neu-
romodulatory system has long been a target to induce plasticity in the adult auditory
cortex (Weinberger, 2004). Tone-evoked shifts in cortical tuning are normally re-
stricted to an early life critical period (Barkat et al., 2011; de Villers-Sidani et al.,
2007); however, robust shifts in the preferred frequency of adult cortical neurons
are achieved by pairing a tone with electrical stimulation of the NB, the main source
of cortical acetylcholine (Froemke et al., 2007; Kilgard and Merzenich, 1998;
Weinberger, 2004).
Strikingly, a brief tone-NB pairing induces a rapid reduction of synaptic inhibi-
tion that persists for hours. This transient disinhibition triggered by cholinergic input
is thought to promote cortical hyperexcitability and allow for reorganization of au-
ditory cortex (Froemke et al., 2007). A recent study has found that pairing vagus
nerve stimulation (VNS) with a tone also drives long-lasting changes in auditory cor-
tical maps (Engineer et al., 2011). Moreover, VNS reverses the degraded auditory
cortical properties and behavioral deficits associated with noise-induced trauma.
VNS may lead to the release of multiple neurotransmitters, including acetycholine.
The cholinergic work in auditory cortex has primarily focused on the muscarinic
subtype of acetylcholine receptors. Indeed, cortical application of the muscarinic re-
ceptor antagonist atropine blocks NB-induced adult plasticity, suggesting an essen-
tial role for this receptor (Weinberger, 2004). However, more recent studies have
5 Critical Period Gating 19
also identified the nicotinic acetylcholine receptor (nAChR) as a regulator of cortical

plasticity (Metherate, 2004). Interestingly, the early developmental periods in audi-
tory cortex coincide with a transient upregulation in nAChRs. During the first few
postnatal weeks, there is a peak in acetylcholinesterase staining, and in the mRNA
expression and binding sites of two predominant cortical nAChR subtypes, a7 and
a4b2 (Metherate, 2004).
As cortical plasticity declines with age, nAChR expression is decreased. In ad-
dition, the function of nAChRs is actively dampened by the developmental upregu-
lation of Lynx1, a membrane-anchored protein that alters nAChR agonist binding
and desensitization kinetics (Miwa et al., 1999). Genetic deletion of Lynx1 enhances
nAChR signaling and heightens plasticity in adult V1 (Morishita et al., 2010). More-
over, adult Lynx1 KO mice can spontaneously recover acuity following an earlier
monocular deprivation during the critical period by simply reopening the closed
eye. Likewise, boosting nicotinic signaling with a cholinesterase inhibitor in adult
WT animals also enables the recovery from amblyopia.
Lynx1 (Morishita et al., 2010) and nAChRs (Arroyo et al., 2012) are expressed on
cortical GABAergic cells and may promote plasticity by adjusting EI balance. Re-
cent work suggests that nAChRs activate the disinhibitory microcircuit (above) in
auditory cortex that is required for fear learning (Letzkus et al., 2011). In the adult
mouse barrel cortex, an upregulation of a4-containing nAChRs on GABAergic neu-
rons mediates the cortical depression associated with whisker trimming (Brown
et al., 2012). Together, these studies strongly implicate nAChR signaling as an im-
portant regulator of cortical plasticity.
Serotonin is one of the first neurotransmitters to appear in the brain (Gaspar et al.,
2003) and is involved in a variety of early developmental processes (Lesch and
Waider, 2012). Serotonergic fibers from the brainstem raphe nuclei broadly inner-
vate the cortex, influencing development of neocortical architecture. Serotonin dys-
function prevents the formation of characteristic barrel fields in the mouse
somatosensory cortex (Persico et al., 2001), and perinatal SSRI exposure alters re-
ceptive field properties in auditory cortex (Simpson et al., 2011). In humans, mater-
nal serotonin levels produce bidirectional shifts in critical periods for infant speech
perception: prenatal SSRI exposure accelerates a critical period for consonant dis-
crimination, while maternal depression (associated with decreased serotonin levels;
Jans et al., 2007) delays the critical period for nonnative sound discrimination
(Weikum et al., 2012).
The serotonergic system has thus become a target to reinstate adult plasticity.
Chronic SSRI treatment reopens a critical period for ocular dominance plasticity
in rat visual cortex and allows recovery of visual acuity from amyblyopia in adult-
hood (Maya Vetencourt et al., 2008, 2011). A similar critical period reactivation oc-
curs in the fear-conditioning network: fear erasure by extinction training, which
normally occurs only in juvenile mice (Gogolla et al, 2009a), is achieved in adults
by chronic SSRI treatment (Karpova et al., 2011). Reactivation of plasticity is asso-
ciated with an SSRI-induced enhancement of LTP (Karpova et al., 2011; Maya
Vetencourt et al., 2008, 2011; Park et al., 2012).
Similar to cholinergic enhancement, SSRIs may act to promote plasticity by reduc-

ing intracortical inhibitory function. Chronic SSRI treatment reduces basal levels of cor-
tical extracellular GABA, and benzodiazepine administration prevents SSRI-induced
adult visual plasticity (Maya Vetencourt et al., 2008). Taken together, these effects
suggest that the successful resetting of EI balance to a juvenile, more plastic state
by endogenous neuromodulator release may underlie the efficacy of noninvasive ap-
proaches to rekindle adult plasticity, such as video-game training (Bavelier et al., 2010).
6 IMPLICATIONS
6.1 Mental Disorders
The realization that critical period timing is itself plastic offers insight into neurode-
velopmental disorders. Targeting these molecular triggers and brakes may offer ther-
apeutic strategies to reinstate plasticity when it is inappropriately timed or fails to
close properly. In the postmortem schizophrenic brain, deficient myelination,
reduced perisomatic GABA synapses, and excessive spine pruning are commonly
observed (Insel, 2010). Moreover, PNNs are compromised in the amygdala and pre-
frontal cortex (Mauney et al., 2013; Pantazopoulos et al., 2010). These are hallmarks
of a brain whose plasticity brakes have not come on fully, suggesting that the failure
to stabilize circuits at least during the prodromal stage may contribute to psychoses.
Mapping the developmental trajectory of critical period plasticity may become an
important diagnostic and potential therapeutic tool.
Likewise, EI imbalance, in particular of PV circuits, has been noted across au-
tism spectrum disorders (Gogolla et al., 2009b; Rubenstein and Merzenich, 2003),
suggesting a mis-timing of critical period onset. Due to the hierarchical nature of
critical periods, even a small jitter in the earliest plastic windows may have a cas-
cading effect on later stages to yield complex cognitive phenotypes. Mouse models
of autism are starting to confirm such timing errors, which encouragingly can be
reversed by rebalancing circuit function. For example, in the Mecp2-deficient mouse
model of Rett syndrome, PV circuits are paradoxically hyper-mature preceding a
regression of cortical function. In the visual cortex, this can be reversed by dark rear-
ing the animals or further genetic disruption of NMDA receptor 2A subunits (Durand
et al., 2012). PV cells are preferentially sensitive to NMDA receptor function, and
low-dose ketamine treatment restores neural activity across brain regions in the
Mecp2 KO mouse (Kron et al., 2012). Other mouse models of autism, such as Fragile
X (Harlow et al., 2010), may instead show an opposite, delayed onset of plasticity
due to impoverished PV cell networks (Gogolla et al., 2009b). This would require
an appropriately timed enhancement of GABA function for rescue.
6.2 Cross-Modal Plasticity

Early blind or deaf subjects are known to re-purpose their deprived cortices to process
other sensory modalities (Kral and Sharma, 2012; Merabet and Pascual-Leone, 2010).
6 Implications 21
Strikingly, this effect declines with later onset of deprivation, while early life rewiring
conversely interferes with later recovery of function if sensory input is restored (Lee
et al., 2001). Inhibitory transmission and plasticity mechanisms are typically kept in a
refractory state of development by exposure to darkness (Huang et al., 2010; Kang
et al., 2013) or rejuvenated by environmental enrichment (Sale et al., 2007; Scali
et al., 2012), suggesting an explanation for these effects in humans.
An elegant animal model exhibiting cross-modal development in response to al-
tered early sensory input is the barn owl (Keuroghlian and Knudsen, 2007). Multi-
modal integration of auditory and visual maps is essential for proper localization and
targeted flight toward an object or prey. The microsecond inter-aural time differ-
ences (ITD) of arriving sounds emitted from a source are superimposed onto the
visual receptive fields in the optic tectum. When misaligned during development,
such as with prism goggles, an aggressive period of rewiring ensues over the follow-
ing weeks to retune ITD preferences to match the displaced visual scene of individual
neurons. This prolonged process is ultimately consolidated by the physical growth of
axons in the direction of the newly acquired tuning.
Notably, there is a further targeted growth of novel inhibitory connections as well
to silence the unused representation in the tectum (Zheng and Knudsen, 1999). In this
manner, the barn owl remains free of confusion while retaining the capacity for mul-
tiple maps to coexist. Indeed, when confronted with an environment that was previ-
ously experienced during the critical period, adult barn owls exhibit rapid and broad
shifts of ITD maps even if they are incapable of acquiring new ones. Similar ability to
shift ocular dominance is observed in adult mice that previously experienced it ear-
lier in life (Hofer et al., 2006). Inhibitory connections in V1 are also strengthened by
monocular deprivation during the critical period (Maffei et al., 2006; Skangiel-
Kramska and Kossut, 1984).
Such dramatic anatomical changes are not observed in adult barn owls
(Linkenhoker et al., 2005). However, the clever use of incremental training procedures
does enable cumulative shifts in ITD tuning even in adult owls (Linkenhoker and
Knudsen, 2002). Moreover, raising them in an enriched environment, such as active
hunting rather than cage rearing (Brainard and Knudsen, 1998), extends the duration
of the critical period. Thus, as in mouse V1, critical period plasticity per se is plastic
and can be tapped noninvasively by engaging environments where perception for ac-
tion is needed. Such strategies have recently been employed in video-game training
approaches to rescue amblyopia in adult humans (Bavelier et al., 2010).
6.3 Higher Cognition

While strict limitations on plasticity may be evident in primary sensory areas, they
gradually become less rigid in higher cognitive domains. So, the ability to hear r
from l may be lost in primary auditory cortex of native Japanese, but the acquisi-
tion of a second language per se is not. Amblyopia may become hard-wired by the
age of 8, but the ability to learn new faces (presumably in area IT) remains. These
observations reveal the remarkable plasticity that is present throughout life in higher
associational brain areas and support the hierarchical nature of critical periods. In-
terestingly, PV circuit maturation follows this gradient along the visual pathway in
primates (Conde et al., 1996).
The adult brain does not process all inputs equally, but learns through experience
that certain events are more likely to occur than others. This Bayesian view further
attests to the importance of establishing early, firm foundations in order to generate
higher cognitive function. A gradient of developmental hard wiring ensures that sta-
ble primary inputs are passed on to generate more flexible associations in higher as-
sociational areas. For example, the expansion of multimodal receptive fields to
encompass tool use in adult monkey parietal cortex is accompanied by significant
anatomical growth of new axons as the animals gradually learn their use over several
weeks (Iriki, 2006; Quallo et al., 2009). Interestingly, such evolutionarily advanced
associational cortices are the least invested in CSPGs and are known to myelinate last
(Braak and Braak, 1996; Bruckner et al, 1999). Thus, the cellular and molecular con-
straints that are present at earlier stages seem to be loosened or absent. Unfortunately,
this lifelong plasticity may not be without consequence, as these regions are prefer-
entially vulnerable to neurodegeneration with age (Mesulam, 1999). Critical period
closure may then also be considered neuroprotective.
7 FUTURE DIRECTIONS
Neural circuits are molded early in life to best represent the sensory input arriving at
that time, and then eventually become hard-wired. The use of a molecular/genetic
approach has revealed that specific GABA circuits orchestrate the functional and
structural rewiring of neural networks during critical periods of cortical plasticity,
which become limited in adulthood by the further expression of brake-like factors.
Ongoing work focuses on (1) confirming to what extent these mechanisms generalize
across brain regions, and (2) translating basic animal research into therapeutic strat-
egies for devastating neurological disorders in humans.
Given the limited environments in which most animals live, critical periods may
have evolved as an effective survival strategy for their relatively short lifespan. Crit-
ical period duration is in fact correlated with average life expectancy (e.g., in V1;
Berardi et al., 2000). However, in the past century, humans have enjoyed a rapid in-
crease in longevity and the ability to drastically change their surroundings on short
timescales. Perhaps our species is now acutely feeling the limitations of critical pe-
riod biologynot only as linguistic awkwardness when immersed in a foreign land,
but more seriously manifest as neuropsychiatric disorders of developmental origin.
In order to leverage these recent insights for lifelong learning, several conse-
quences should be explored further:
(1) Individual variability in critical period timing. Appreciating the powerful role of
EI circuit balance (in particular, one class of GABA neuron) and its sensitivity
References 23
to early exposure to drugs, adversity, sleep, or genetic perturbation predicts that

optimal plasticity windows will differ across individuals. A striking example
may be the mis-regulation of EI balance in autism or after early life seizures,
suggesting careful mapping of critical period timing is needed in patient
populations.
(2) Lifting brakes in adulthood. The realization that the brains intrinsic potential for
plasticity is actively dampened by brake-like factors has overturned the
traditional view of a fixed, immutable circuitry that is consolidated early in life.
At the same time, the great biological cost to maintain multiple brakes
throughout life emphasizes the need to stabilize circuits for proper brain
function. Understanding why there are so many, how they interact, and
ultimately how to lift them in noninvasive ways may hold the keys to lifelong
learning.
Acknowledgments
Supported by the Canadian Institute for Advanced Research (A. E. T., T. K. H.) and the Nancy
Lurie Marks Family Foundation (A. E. T.).
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CHAPTER

(1) Excitatoryinhibitory (EI) circuit balance is a trigger. The classical

is intrinsically plastic, and one of the outcomes of normal development is then to

2 CRITICAL PERIODS: PRUNING CIRCUITS

3 CRITICAL PERIOD PLASTICITY OF EXCITATORY

3.1 Excitatory Circuit Plasticity During Critical Periods

3.2 Inhibitory Circuit Plasticity During Critical Periods

4 CRITICAL PERIOD TRIGGERS AND BRAKES

Only a1-containing GABAA receptors, which are preferentially expressed and

4.2 Brain-derived neurotrophic factor

4.3 Extracellular Matrix: PNNs and Otx2

lattice-like structures surround cell bodies and proximal neurites, preferentially

4.5 Myelin and Myelin-Associated Inhibitors

4.6 Epigenetic Regulation

catalyzed by DNA methyltransferases. DNA methylation represses transcription

5 CRITICAL PERIOD GATING

5.2 Modulation of PV Circuits

also identified the nicotinic acetylcholine receptor (nAChR) as a regulator of cortical

Similar to cholinergic enhancement, SSRIs may act to promote plasticity by reduc-

6.2 Cross-Modal Plasticity

6.3 Higher Cognition

to early exposure to drugs, adversity, sleep, or genetic perturbation predicts that

Insel, T.R., 2010. Rethinking schizophrenia. Nature 468 (7321), 187193.

DNA demethylation mediates gene-childhood trauma interactions. Nat. Neurosci. 16,

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