A characteristic of the developing mammalian visual system is a brief interval of plasticity, termed the "critical period," when the circuitry of primary visual cortex is most sensitive to perturbation of visual experience. Depriving one eye of vision (monocular deprivation [MD]) during the critical period alters ocular dominance (OD) by shifting the responsiveness of neurons in visual cortex to favor the nondeprived eye. A disinhibitory microcircuit involving parvalbumin-expressing (PV) interneurons initiates this OD plasticity. The gene encoding the neuronal nogo-66-receptor 1 (ngr1/rtn4r) is required to close the critical period. Here we combined mouse genetics, electrophysiology, and circuit mapping with laser-scanning photostimulation to investigate whether disinhibition is confined to the critical period by ngr1 We demonstrate that ngr1 mutant mice retain plasticity characteristic of the critical period as adults, and that ngr1 operates within PV interneurons to restrict the loss of intracortical excitatory synaptic input following MD in adult mice, and this disinhibition induces a "lower PV network configuration" in both critical-period wild-type mice and adult ngr1^-/- mice. We propose that ngr1 limits disinhibition to close the critical period for OD plasticity and that a decrease in PV expression levels reports the diminished recent cumulative activity of these interneurons.

Significance statement

Life experience refines brain circuits throughout development during specified critical periods. Abnormal experience during these critical periods can yield enduring maladaptive changes in neural circuits that impair brain function. In the developing visual system, visual deprivation early in life can result in amblyopia (lazy-eye), a prevalent childhood disorder comprising permanent deficits in spatial vision. Here we identify that the nogo-66 receptor 1 gene restricts an early and essential step in OD plasticity to the critical period. These findings link the emerging circuit-level description of OD plasticity to the genetic regulation of the critical period. Understanding how plasticity is confined to critical periods may provide clues how to better treat amblyopia.

Disrupting binocular vision during a developmental critical period can yield enduring changes to ocular dominance (OD) in primary visual cortex (V1). Here we investigated how this experience-dependent plasticity is coordinated within the laminar circuitry of V1 by deleting separately in each cortical layer (L) a gene required to close the critical period, nogo-66 receptor (ngr1). Deleting ngr1 in excitatory neurons in L4, but not in L2/3, L5, or L6, prevented closure of the critical period, and adult mice remained sensitive to brief monocular deprivation. Intracortical disinhibition, but not thalamocortical disinhibition, accompanied this OD plasticity. Both juvenile wild-type mice and adult mice lacking ngr1 in L4 displayed OD plasticity that advanced more rapidly L4 than L2/3 or L5. Interestingly, blocking OD plasticity in L2/3 with the drug AM-251 did not impair OD plasticity in L5. We propose that L4 restricts disinhibition and gates OD plasticity independent of a canonical cortical microcircuit.