The role of Arc in the experience-dependent development of the visual cortex

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Project Summary Neuronal activity, driven by experience, leads to rapid refinement of the connections in the newborn brain through the mechanisms of synaptic plasticity. Defects in sensory experience during development can lead to a lifelong impairment in sensory perception, such as in amblyopia. Additionally, dysfunction in synaptic plasticity during key windows of development can lead to neurodevelopmental disorders such as Angelman syndrome, Fragile-X syndrome, and schizophrenia. Understanding the role and mechanisms of experience dependent plasticity in development is therefore crucial to treating these disorders. Arc is an immediate early gene rapidly transcribed and translated in response to neuronal activity that mediates functional and structural changes at excitatory synapses. Arc is required for experience-dependent synaptic plasticity in the visual cortex. However, the role of Arc in the experience-dependent refinement and structural synaptic changes that occur during development in the visual cortex is unknown. This proposal seeks to test the hypothesis that Arc- dependent AMPA receptor endocytosis and synapse elimination are required for the experience dependent development of the visual cortex. Aim 1 will determine the role of Arc in the development of visual response properties of visual cortex neurons. In part 1, in vivo two-photon calcium imaging will be used to record visually evoked responses in the visual cortex of wild type and Arc KO mice during development. Visual responses are known to develop in distinct stages during early life in an experience dependent way, and the prediction is that Arc is necessary for this process, and therefore Arc KO mice will fail to have this development of visual responses. Part 2 will determine the molecular mechanisms of Arc’s role in mediating experience-dependent refinement of the visual cortex during development. The hypothesis that Arc-dependent AMPAR endocytosis is required in vivo will be tested through a viral rescue strategy. This approach uses viral expression of wild type or mutant Arc in the visual cortex of Arc KO mice, and determines whether the development of normal visual response properties occurs by using two-photon calcium imaging. Aim 2 will address the role of Arc in the structural changes of dendritic spines that occur during monocular deprivation and normal development. The hypothesis is that Arc is necessary for spine elimination during monocular deprivation and development. These two aims will elucidate the role of Arc in structural and functional synaptic plasticity that underlies the development of the visual cortex.