Role of local interneurons in early cortical dysfunction in Shank3 KO mice

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PROJECT SUMMARY Epilepsy and epileptiform patterns of neural activity are extremely prevalent in autism spectrum disorders (ASD) but the specific mechanisms underlying the emergence of cortical hyperactivity in these conditions remain largely unknown. Several physiological and morphological abnormalities in cortical GABAergic interneurons have been observed in both autistic individuals and mouse models of autism, suggesting that cortical interneuron dysfunction might be a critical factor underlying cortical activity imbalances in ASD. We have recently shown that mice with deletions in Shank3 exhibit cortical hyperactivity during early postnatal development. Loss of Shank3 results in reduced interneuron activity in response to sensory stimulation in adult stages, but whether similar phenotypes are present early in development, when cortical hyperactivity emerges, remains unknown. We hypothesize that loss of Shank3 and subsequent reduction of glutamatergic drive in cortical interneurons is a primary cause of early cortical hyperactivity in Shank3 KO mice. To test this hypothesis we will use whole-cell electrophysiology and 2-photon microcopy techniques optimized for studies in developing mice, and characterize the physiological properties of Shank3 KO cortical Parvalbumin (PV) and Somatostatin (SST)-positive interneurons, the two major populations of inhibitory interneurons. This effort will identify a potential primary pathophysiological abnormality underlying early cortical hyperactivity in ASD that will guide the development of new therapeutic strategies that restore optimal network function during critical periods of cortical development.