Neural Circuit Pathology Driven by <i>Shank3</i> Mutation Disrupts Social Behaviors

Abstract

Loss of sociability is a core symptom in autism spectrum disorder (ASD) that may arise from neural network dysconnectivity between multiple brain regions contributing to social behaviors. However, the pathogenic neural network mechanisms underlying social dysfunction of ASD are largely unknown. Here, we demonstrate that the circuit-selective mutation of ASD-risk Shank3 gene within a unidirectional neural circuit from the prefrontal cortex to the basolateral amygdala reduces sociability as well as elevates the neural activity and its amplitude-variability in the circuit, which is consistent with the neuroimaging results from human ASD patients. Moreover, the abnormal neural circuit activities reduce the temporal correlation of socially-tuned neurons to the events of social interactions and alter the intra-circuit functional network involved in social behaviors. Finally, optogenetic mimicry of the circuit hyperactivity recapitulates the reduced sociability of Shank3 ctMUT mice. Collectively these results highlight a circuit-level pathogenic mechanism of Shank3 mutation that drives social dysfunction