Loss of the autism associated gene Tbr1 disrupts prediction and encoding by prefrontal ensembles during socioemotional behaviors

Disruptions in many genes linked to autism spectrum disorder (ASD) affect synaptic function and socioemotional behaviors in mice. However, exactly how synaptic dysfunction alters neural activity patterns underlying behavior remains unknown. We addressed this using mice lacking the high confidence ASD gene Tbr1 in cortical layer 5 (L5) projection neurons (Tbr1 cKO mice). These mice have known deficits in synaptic input to L5 neurons and social behavior. We also find some abnormalities in anxiety-related avoidance. Calcium imaging of prefrontal L5 neurons revealed that despite reduced overall activity, cKO mice recruit normal numbers of neurons into prefrontal ensembles encoding social and anxiety-related behaviors. However, the stability, inter-neuronal coordination, and reactivation of social ensembles were diminished in cKO mice. Furthermore, in cKO mice, ensembles no longer predicted approach-avoidance decisions. These results reveal new aspects of how prefrontal ensembles encode socioemotional behaviors, and malfunction in the setting of ASD-linked gene disruption.