Critical period plasticity in local cortical circuits

Key Points

  • Critical periods of brain development have been identified across sensory systems, but are best characterized in the visual cortex where the inputs from the two eyes first converge and compete for space, both functionally and structurally. In children born with opacity or deviation of the eyes, the consequent loss of cortical spiking response to the deprived eye (ocular dominance plasticity) leads to lifelong amblyopia (although the retina may remain healthy). Critical periods for other receptive field properties (for example, orientation bias or visual motion) might vary in their developmental timing.

  • Although in vitro models of excitatory homosynaptic plasticity have been doubly dissociated from ocular dominance changes in vivo, genetic or pharmacological manipulation of the development of GABA (γ-aminobutyric acid)-mediated transmission yields consistent and direct control over critical period timing and its eventual anatomical outcomes (such as spine pruning and column spacing).

  • Several lines of evidence implicate one particular GABA-containing cell type — the parvalbumin-positive large basket cell — as the critical period trigger. (1) They develop with a late postnatal time course in tight correlation with plasticity onset; (2) brain-derived neurotrophic factor (BDNF) accelerates the onset of both development and plasticity; (3) dark-rearing delays the onset of both; (4) they make somatic synapses containing GABAA (GABA type A) receptor α1-subunits, which mediate critical period acceleration by benzodiazepines; (5) their ability to fire at high rates determines the rate of plasticity; (6) their long, horizontal axons span and can influence ocular dominance column size; and (7) with age they are preferentially enwrapped by perineuronal nets, the removal of which in adulthood (by chondroitinases) reactivates plasticity.

  • After induction by GABA cell development, critical period expression follows a molecular cascade leading toward structural refinement through the actions of proteases and neurotrophins. Proteolytic (tissue-type plasminogen activator, tPA) action increases on sensory deprivation, leading, during the critical period only, to dendritic spine motility, pruning, and axonal retraction followed by growth.

  • How might GABA circuits trigger plasticity in vivo? Two heuristic models are proposed. First, 'instructive' editing of back-propagating action potentials at the soma to control synaptic plasticity in the dendrites. Second, 'permissive' synchrony detection as a network of parvalbumin-positive cells coupled by gap junctions and mutual inhibitory connections to regulate the release and uptake of proteases and growth factors. In this case, competition occurs extracellularly.

  • The article also discusses a general role for local circuit inhibition in the experience-dependent development of other brain systems.


Neuronal circuits in the brain are shaped by experience during 'critical periods' in early postnatal life. In the primary visual cortex, this activity-dependent development is triggered by the functional maturation of local inhibitory connections and driven by a specific, late-developing subset of interneurons. Ultimately, the structural consolidation of competing sensory inputs is mediated by a proteolytic reorganization of the extracellular matrix that occurs only during the critical period. The reactivation of this process, and subsequent recovery of function in conditions such as amblyopia, can now be studied with realistic circuit models that might generalize across systems.

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Figure 1: Local circuit control of developing columnar architecture in the neocortex.
Figure 2: GABA-mediated control of the critical period.
Figure 3: Heterogeneity of local GABA circuits in the neocortex.
Figure 4: Specific GABAA circuits for visual cortical plasticity.
Figure 5: Structural consolidation during the critical period.
Figure 6: Molecular mechanisms of visual cortical plasticity.
Figure 7: Two models for inhibitory control of sensory plasticity.


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I thank M. Fagiolini for comments, N. Mataga for immunostaining in Figure 5b and all members of the lab for Neuronal Circuit Development (RIKEN BSI) for their dedication to understanding critical period mechanisms.

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Entrez Gene






Rett syndrome

Tourette's syndrome


RIKEN Brain Science Institute



A strict time window during which experience provides information that is essential for normal development and permanently alters performance.


A limited time during development, during which the effect of experience on brain function is particularly strong.


Poor vision through an eye that is otherwise physically healthy due to little or no transmission of the visual image to the brain through circuits that are hard-wired during a developmental critical period. It affects 2–5% of the population.


Relative anatomical or physiological strength of connections from either eye to individual cells in the primary visual cortex.


Axons from the thalamus (for example, the dLGN) that relay sensory input from the periphery (for example, the retina) to layer 4 of the neocortex.


Modulate chloride flux through GABAA receptors that contain the γ2 and any combination of α1, α2, α3 or α5 subunits. Benzodiazepine agonists enhance and inverse agonists decrease GABA efficacy.


Deviation of the two eyes due to a weakening of extraocular musculature that results in either an inward (esotropic) or outward (exotropic) rotation of one orbit and consequent amblyopia.


(TTX). A voltage-dependent sodium channel blocker that can be used to silence all neural activity except spontaneous neurotransmitter release.


(MD). Imbalanced visual input due to the occlusion of one eye by patching, eyelid suture or intraocular TTX injection.


One of three calcium-binding proteins, which, together with calretinin and calbindin, are expressed in most GABA-mediated neurons in the neocortex in largely non-overlapping groups.


Ability of parvalbumin-positive cells to fire non-adapting action potentials at rates of up to several hundred Hertz, due, in part, to unique potassium conductances (Kv3 class).


Stereotypical GABA cell of the cerebral cortex that ensheathes the axon initial segment of up to 200 pyramidal cells with 'cartridge' synapses to directly control action potential generation.


Class of GABA cell with long, horizontally-extending axon that makes potent inhibitory contacts on the soma and proximal parts of the dendrites of target pyramidal cells.


(CCK). A neuropeptide that is found in non-fast-spiking large basket cells that contact the soma of target pyramidal cells at synapses enriched in GABAA receptor α2-subunits.


A conglomeration of chondroitin sulphate proteoglycans, extracellular matrix and cell-adhesion molecules that condenses around particular large-basket cells with age.


(tPA). The major serine protease in the brain, well known as an anti-clotting agent that works by cleaving fibrin in the blood.


Transcription factors that are induced within minutes of intense neuronal activity. Examples include zif268 and c-fos.


The active form of plasminogen, which is the primary target of tPA action, and itself a protease that is known to cleave extracellular matrix molecules (for example, laminin and phosphacan).


(LTD). A persistent reduction of synaptic transmission in response to weak, poorly-correlated input.


(LTP). A persistent strengthening of synaptic transmission in response to strong, correlated input.


Describes physiological windows for LTP or LTD of synaptic transmission based on the arrival time of incoming action potentials with respect to back-propagated spikes in the target dendrite.


(PKA). Phosphorylates multiple targets (including AMPA and GABAA receptors) when cyclic AMP binds its regulatory subunits to release the catalytic domains.

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Hensch, T. Critical period plasticity in local cortical circuits. Nat Rev Neurosci 6, 877–888 (2005).

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