Impaired Spatiotemporal Encoding of Social Behavior and Anxiety in the Prefrontal Cortex of Mice Lacking ASD-Risk Gene Shank3

The prefrontal cortex is a central regulator of complex behaviors, including social interaction and anxiety-related behaviors. The prefrontal cortex encodes these behaviors using heterogeneous groups of neurons, or ensembles, which collectively process inputs and communicate with distributed brain regions. We examined whether loss of the Autism-risk gene Shank3 alters the recruitment of neurons encoding socioemotional behavior collectively, or if abnormal activity during specific behaviors might affect functionally or anatomically defined populations of neurons. To do this, we combined spatially-resolved microendoscopic calcium imaging across the prefrontal microcircuit with functionally defined labeling of neurons as control and mutant mice engaged in social interaction or anxiety-provoking behaviors. We then utilized a non-biased transcriptomic method to identify neurons activated by social interactions. We show that the recruitment of heterogeneous neuronal populations are altered in a cell type and spatially dependent manner by loss of Shank3, with impaired recruitment of behavior-specific activity patterns within superficial, but not deeper aspects of the prefrontal cortex.