Mendez-Vazquez, Hadassah, authorKim, Seonil, advisorTamkun, Michael, committee memberMyers, Brent, committee memberChanda, Soham, committee member2023-08-282023-08-282023https://hdl.handle.net/10217/236907Social impairment is a key symptom of several neuropsychiatric disorders, including autism spectrum disorder (ASD), anxiety, depression, and schizophrenia. Despite the increasing prevalence of these disorders the physiological, cellular, and molecular factors underlying social dysfunction are still poorly understood. In humans, mutations in the δ-catenin gene have been linked to severe forms of ASD. δ-catenin is a post-synaptic scaffolding protein that is expressed in excitatory synapses and functions as an anchor for N-cadherin and the AMPA receptor (AMPAR) subunit GluA2 at the postsynaptic density. A glycine 34 to serine (G34S) mutation in the δ-catenin gene was identified in ASD patients and induces a loss of δ-catenin function, which may mediate ASD pathogenesis. The mechanism by which this G34S mutation causes loss of δ-catenin function to induce ASD remains unclear. Initial findings revealed that the G34S mutation increases glycogen synthase kinase 3β (GSK3β)-dependent δ-catenin degradation to reduce δ-catenin levels. Moreover, we found that mice possessing the G34S δ-catenin mutation have significantly reduced synaptic cortical δ-catenin and GluA2 levels. The G34S mutation was also found to differentially alter glutamatergic activity in cortical excitatory and inhibitory cells. Furthermore, G34S δ-catenin mutant mice exhibit markedly impaired social behavior, which is a characteristic feature of ASD. Most significantly, we found that inhibition of GSK3β is sufficient to reverse the G34S-induced loss of δ-catenin function in cells and mice. Altogether, our study reveals that the loss of δ-catenin function arising from the ASD-associated G34S mutation induces social dysfunction via disruptions in glutamatergic activity, and that GSK3β inhibition can reverse abnormal δ-catenin G34S-induced glutamatergic activity and social deficits.born digitalmasters thesesengCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.social behaviorautismsynapseText