The roles of delta-catenin in social behavior - Many species depend on social activity to thrive, and social impairment is a fundamental symptom of several mental diseases. According to research, synaptic signals and activity can control social behavior. Yet, it is still unclear how synapse control and social behavior are related. δ-catenin functions as an anchor for the glutamatergic AMPA receptor (AMPARs) to regulate synaptic activity in excitatory synapses. Several families with autism have been identified to have mutations in the δ-catenin gene, which results in a loss of δ-catenin functions at excitatory synapses and is thought to be the etiology of autism in people. Recent studies, including our own, suggest that the loss of δ-catenin functions significantly decreases cortical neurons' inhibition to increase excitation. Our new data further reveal that δ-catenin deficiency disrupts social behavior in mice. These new findings strongly support the scientific premise that δ-catenin is critical for glutamatergic synaptic activity and social behavior. Nonetheless, the δ-catenin-mediated link of synaptic, cellular, and neural substrates to social behavior is understudied. The significance of the current proposal is thus predicated on filling this gap. Postsynaptic glutamatergic activity in excitatory and inhibitory cells in the medial prefrontal cortex (mPFC) regulates cellular excitation and inhibition to control prefrontal rhythmic activity patterns, which is essential in the control of social behavior in humans and animals. However prior research on the neural basis of social behavior has mostly concentrated on top-down mPFC projections to various subcortical regions. Hence, in these earlier studies, glutamatergic inputs to prefrontal neurons were mainly disregarded. Therefore, it is unclear how the postsynaptic glutamatergic activity of prefrontal cells relates to social behavior. Research suggests that parvalbumin-positive (PV+) inhibitory interneurons in the mPFC receive direct glutamatergic inputs from multiple subcortical regions to provide feedforward inhibition onto prefrontal pyramidal neurons and control network activity. This is important for the regulation of social behavior. Our preliminary data suggest that δ-catenin deficiency impairs prefrontal neural activity at cellular and network levels to induce social deficits. Therefore, existing data and our new findings lead us to hypothesize that δ-catenin is important for glutamatergic activity in PV+ inhibitory interneurons to provide feedforward inhibition onto pyramidal neurons in the mPFC, which regulates prefrontal activity at the cellular and network levels to ensure normal social behavior. We will employ two new mouse models of δ-catenin deficiency - δ-catenin KO mice and human ASD-associated δ-catenin glycine 34 to serine (G34S) mutant mice – to examine if δ-catenin controls pathway-specific glutamatergic activity in PV+ interneurons and feedforward inhibition onto pyramidal neurons in the mPFC (Aim 1), to determine whether δ-catenin deficiency disrupts prefrontal network activity during social interaction (Aim 2), and to address if altering prefrontal δ-catenin expression is sufficient to affect social behavior (Aim 3).
