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.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Central Visual Processing Study Section (CVP)
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Steinmetz, Michael A
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Brandeis University
Schools of Arts and Sciences
United States
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Turrigiano, Gina G (2017) The dialectic of Hebb and homeostasis. Philos Trans R Soc Lond B Biol Sci 372:
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Nahmani, Marc; Turrigiano, Gina G (2014) Deprivation-induced strengthening of presynaptic and postsynaptic inhibitory transmission in layer 4 of visual cortex during the critical period. J Neurosci 34:2571-82
Nahmani, M; Turrigiano, G G (2014) Adult cortical plasticity following injury: Recapitulation of critical period mechanisms? Neuroscience 283:4-16
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Lefort, Sandrine; Gray, Annette C; Turrigiano, Gina G (2013) Long-term inhibitory plasticity in visual cortical layer 4 switches sign at the opening of the critical period. Proc Natl Acad Sci U S A 110:E4540-7
Nataraj, Kiran; Turrigiano, Gina (2011) Regional and temporal specificity of intrinsic plasticity mechanisms in rodent primary visual cortex. J Neurosci 31:17932-40
Turrigiano, Gina (2011) Too many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement. Annu Rev Neurosci 34:89-103
Nataraj, Kiran; Le Roux, Nicolas; Nahmani, Marc et al. (2010) Visual deprivation suppresses L5 pyramidal neuron excitability by preventing the induction of intrinsic plasticity. Neuron 68:750-62
Maffei, Arianna; Lambo, Mary E; Turrigiano, Gina G (2010) Critical period for inhibitory plasticity in rodent binocular V1. J Neurosci 30:3304-9

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