The proper functioning of the mature mammalian visual system depends upon experience-dependent refinement of cortical circuitry during early postnatal development. Visual deprivation during this early "critical period" (CP) can lead to a major degradation of visual function. Despite decades of research it is still unclear which cellular plasticity mechanism(s) contribute to this loss of visual function, and by extension are required for the normal development of visual response properties. Recently the maturation of inhibition from fast-spiking GABAergic basket cells (FS cells) has been implicated in the regulation of CP onset, but why mature inhibition is necessary for CP plasticity is still unknown. In the past funding period we found that monocular deprivation (MD) during the rodent CP dramatically potentiates inhibitory transmission at FS synapses onto star pyramidal neurons within layer 4, by inducing a novel form of long-term potentiation of inhibition (LTPi) at this synapse. Further, LTPi is developmentally regulated, and turns on coincidently with the opening of the CP. In this proposal we wish to test the hypothesis that the classical CP is triggered by the maturation of plasticity at FS synapses, and that LTPi plays a central role in the loss of visual responsiveness induced by visual deprivation. To this end we will explore the expression and induction mechanisms and developmental regulation of LTPi, and develop tools that will allow us to block LTPi in vivo to determine the role of LTPi in MD-induced loss of visual responsiveness within layer 4. These experiments will provide novel insight into the mechanisms that control developmental windows of plasticity, and ultimately may generate tools for manipulating this plasticity to generate therapies for amblyopia. PUBLIC HEALTH RELEVANCE: In humans childhood cataracts can severely degrade visual function, even when removed at an early age. Understanding the plasticity mechanisms that underlie the normal experience-dependent development of the visual system, and that also underlie the pathological changes that follow visual deprivation, will provide important therapies for treating childhood cataracts and for reversing the effects of early deprivation. Further, many aspects of child development are subject to developmental sensitive periods, and understanding the mechanisms that generate these sensitive periods and turn them on and off, is likely to have important public policy implications.