Cell-type-specific disruption of nucleus accumbens social representations in a mouse model of autism.

How cell-type-specific nucleus accumbens (NAc) circuits encode social interactions, and whether this encoding is disrupted in autism spectrum disorder (ASD), remains unresolved. Using longitudinal miniscope calcium imaging and optogenetics in mice, we show that NAc core population activity selectively encodes social interaction and that NAc inhibition enhances sociability. In Cntnap2-/- mice, both acute and cross-day social representations are degraded, and NAc inhibition persistently improves sociability. Cell-type-specific recordings and optogenetics reveal opposing medium spiny neuron (MSN) contributions: D1-MSNs promote sociability, and D2-MSNs suppress it. Cntnap2-/- mice exhibit selective depletion of socially excited D1-MSNs and socially inhibited D2-MSNs, along with impaired cross-day population decoding. D2-MSN inhibition improves social behavior in Cntnap2-/- mice, and D1-MSN activation does not. Together, these findings link disrupted, cell-type-specific NAc social representations to ASD-related social dysfunction and suggest that targeted modulation of NAc activity may improve social behavior.