Autism associated mutation in Cacna1d causes perseverative behavioral phenotype in mice

Abstract Behavioral inflexibility and perseveration are core features of autism spectrum disorder and are frequently modeled in mice using reversal learning and repetitive behavior assays. Mutations in CACNA1D , which encodes the L-type calcium channel Cav1.3, have been linked to autism, yet their behavioral consequences remain incompletely characterized. We examined mice carrying the autism-associated Cacna1d G407R gain-of-function mutation across a battery of assays assessing learning, flexibility, and repetitive behavior. Mutant mice learned spatial discriminations and instrumental contingencies at rates comparable to wild-type controls but exhibited deficits during reversal learning following intermediate and extended overtraining, as well as under probabilistic reinforcement. Across ethological assays, mutant mice showed increased grooming, marble burying, and nestlet shredding, consistent with enhanced perseverative behavior. Anxiety-related measures and general locomotion were largely unaffected. These results identify Cav1.3 gain-of-function as a selective regulator of behavioral flexibility and support a role for calcium-dependent corticostriatal plasticity in autism-associated perseveration.