Lower Striatal and Cortical Calretinin Interneuron Density Associated With Altered Social Behavior in Cntnap2...

Variants in the CNTNAP2 gene, encoding the cell adhesion molecule CASPR2, have been identified as genetic risk factors for autism spectrum disorder (ASD). However, the mechanisms through which CNTNAP2 dysfunction alters circuit function remain unknown. Interneurons, as key regulators of excitatory-inhibitory balance, represent a candidate source of vulnerability. In this study, we quantified calretinin-positive (CR+) and parvalbumin-positive (PV+) interneuron density in the caudoputamen (CP) and somatosensory cortex (SSC) of Cntnap2 knockout (KO) and wild-type (WT) mice and assessed their relationship with social behavior. Cntnap2 KO mice exhibited significantly lower CR+ interneuron density in both brain regions, whereas no significant difference was observed in the PV+ density. Cntnap2 KO females showed altered behavior in the social novelty preference test compared to WT females. Cntnap2 KO animals also displayed elevated "moving away" responses, a social withdrawal phenotype. Correlation analyses revealed that within the KO group, higher striatal CR+ density was associated with a greater frequency and duration of "moving away." CR+ density in the SSC did not correlate with this behavioral phenotype. The results suggest that striatal CR+ interneurons may modulate the persistence and intensity of social withdrawal behavior. In conclusion, our findings reveal region-specific alterations in CR+ interneuron density in Cntnap2 KO mice and uncover a previously unrecognized link between Cntnap2 function, striatal interneuron organization and social withdrawal behavior. The results highlight CR+ interneurons as potential contributors to altered basal ganglia function in ASD and underscore the need for circuit-level analyses of genetically defined risk models.