Exploring the role of Cav3.2 calcium channels in autism-like cognitive behavior induced by prenatal valproic acid exposure

Abstract

Recent findings indicated that CACNA1H mutations may contribute to Autism Spectrum Disorder (ASD) by reducing Cav3.2 activity, disrupting neuronal function, and brain development. To explore how Cav3.2 deficiency affects autism-related cognition, we induced autism-like behaviors in wild-type (WT) and Cav3.2 knockout mice (KO) using the prenatal valproic acid model (pre-VPA). We analyzed how cognitive behavior (repetitive behavior, spatial working memory, sociability, social preference, and anxiety) in this model is differentially impacted in WT and Cav3.2 KO mice of different sexes and ages. In WT mice, pre-VPA increased repetitive behavior and self-grooming (>75 %). In contrast, there was no pre-VPA-induced increase in repetitive behavior in Cav3.2 KO male mice, and there was a reduction in self-grooming in adult KO females (∼40 %). While pre-VPA impaired spatial working memory in wild-type adult mice of both sexes, Cav3.2 KO mice were protected. Pre-VPA also induced sociability and social preference deficits in WT mice of both sexes. Deletion of Cav3.2 rescued sociability deficits in juvenile and adult male but not female mice. In addition, Cav3.2 channels appeared to contribute to social preference impairment in juvenile male KO mice and both sexes in adulthood. Additionally, KO mice exposed to pre-VPA exhibited lower anxiety levels in the elevated plus maze test when compared to KO controls. Together, our results provide new insights into the role of Cav3.2 channels in ASD-related behavior and suggest that these channels contribute to a range of behavioral deficits.