Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication deficits, accompanied by restricted and repetitive behaviors. ASD is a lifelong condition that causes a heavy medical and societal burden. To date, there are no disease-modifying, mechanism-targeted treatments approved for core ASD symptoms. In human studies, loss-of-function mutations in the CACNA1H gene, which encodes the T type Cav3.2 calcium channel, have been associated with ASD. However, animal and molecular studies investigating the underlying mechanism in ASD patients with CACNA1H mutations are lacking. In this study, we performed a series of behavioral assays to phenotype the Cav3.2 systemic knockout (Cav3.2KO) mice. The Cav3.2KO mice exhibited ASD-like behaviors, including impaired social novelty, increased self-grooming behavior, and deficits in recognition and retrieval of fear memory. Notably, enhancing γ-aminobutyric acid (GABA) signaling via administration a low-dose of clonazepam (CLZ) rescued these behavioral impairments in the Cav3.2KO mice. Furthermore, we found that the intrinsic GABA level was significantly reduced in the frontal cortex of Cav3.2KO mice, suggesting that GABA transmission was impaired in the Cav3.2KO mice. Together, our findings suggest that loss-of-function in the Cav3.2 channel contributes to ASD-like phenotypes through disrupted GABAergic signaling and that pharmacological enhancement of GABAergic signaling may offer a potential therapeutic approach for individuals with ASD carrying the CACNA1H mutations.