Monday, June 5, 2023
6/5/2023
PROJECT SUMMARY Despite increasing knowledge of the genetic underpinnings of autism risk, the specific pathogenic mechanisms underlying the emergence of motor and cognitive deficits in autism spectrum disorders (ASD) remain unclear. Recent imaging and genetic studies have pointed to corticostriatal dysfunction has a prevalent pathophysiology in ASD. In particular, hypertrophy and abnormal functional connectivity of prefrontal cortex (PFC) and dorsomedial striatum (DMS) have been reported in multiple autistic individuals, providing a potential neuropathological substrate for the repetitive behaviors and social deficits associated with autism. Our laboratory has shown that mice with loss of function deletions in SHANK3 (Shank3B-/-), a highly penetrant monogenic cause of autism, exhibit hyperactivity and abnormal patterns of connectivity in corticostriatal circuits during postnatal development. Behavioral deficits in these animals also emerge during these early developmental periods, suggesting that early corticostriatal dysfunction might be an important pathogenic mechanism in SHANK3 associated disorders. Here we propose to further characterize how striatal circuit development is impaired by loss of Shank3 and identify the specific corticostriatal pathways affected in these conditions (Aim1). In addition, using recently developed conditional transgenic mice that allow cell-specific manipulation of Shank3 expression we will dissect the specific mechanisms leading to corticostriatal connectivity abnormalities (Aim 2). In addition, using new molecular strategies that normalize early excitatory drive in striatal neurons, we will determine the pathogenic role of early striatal circuit dysfunction in the emergence of maladaptive behaviors in Shank3B-/- mice (Aim 3). This work will advance our understanding of the basic mechanisms and developmental rules regulating the maturation of corticostriatal circuits and provide important insights into the pathogenesis of ASD and other neurodevelopmental disorders with early activity imbalances in corticostriatal circuits.
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