NORMAL COGNITIVE FUNCTION AND SOCIAL BEHAVIOR IN HETEROZYGOUS TOTTERING<SUP>TG/- </SUP>MICE

Episodic ataxia type 2 (EA2) is a rare, autosomal dominant inherited neurological disorder characterized by recurrent episodes of motor incoordination, instability and permanent ataxia. EA2 is caused by loss-of-function mutations in the gene CACNA1A, which encodes the pore-forming α₁ subunit of the P/Q-type voltage-gated calcium channel (Ca_V2.1), leading to a loss of P/Q-type calcium channel activity and dysfunction of cerebellar Purkinje cells (PCs). In addition to motor deficits, EA2 patients frequently exhibit cognitive dysfunction in attention, working memory, visual and figural memory, executive functions, and psychiatric symptoms including attention deficit hyperactivity disorder (ADHD), anxiety and personality disorders, psychosis, autism, schizophrenia and depression. However, the pathophysiology underlying cognitive dysfunction in EA2 remains unclear. To address this, we examined cognitive and social behavior in the heterozygous EA2 mouse model tottering^tg/-, carrying a spontaneous mutation in the Cacna1a gene. Unlike homozygous tottering^tg/tg mice, heterozygous animals do not demonstrate motor dysfunction, allowing assessment of cognition independently of ataxia and dystonia. Our EA2 mouse model tottering^tg/- displayed equal anxiety behavior in the open field test, novelty suppressed feeding test and light/dark place preference test, no memory impairments in the object location memory test, novel object recognition test, T-maze test, Barnes maze and Morris water maze, and showed normal social interaction in the three-chamber sociability and three-chamber social interaction test across multiple age groups (3-5, 6-7, 8-10, and >12 months) compared to littermate control tottering^-/- mice. Our results indicate that heterozygous Cacna1a mutations alone are insufficient to induce cognitive or social impairments.