Dietary restriction mitigates cognitive impairments in a mouse model of SCA19/22

Spinocerebellar ataxia types 19 and 22 (SCA19/22) are neurodegenerative disorders caused by mutations in KCND3 (potassium voltage-gated channel subfamily D member 3). Previous studies have developed Kcnd3 F227del knock-in (KI) mice that successfully recapitulate the motor deficits and molecular pathogenesis observed in patients. However, the broader neurobehavioral consequences of the humanized Kcnd3 F227del mutation, and whether these phenotypes depend on functional Kcnd3, remain unclear. In this study, we employed a battery of behavioral assessments and found that the Kcnd3 F227del mutation may not only result in a loss of function but also act as a dominant, toxic gain-of-function variant associated with both ataxia and memory impairments. In contrast, Kcnd3 null mice exhibited primarily hyperactivity without major cognitive deficits. Furthermore, we demonstrated that dietary restriction (DR) effectively attenuates memory deficits but does not improve locomotor impairments in Kcnd3 F227del KI mice at behavioral, cellular, and neurostructural levels. Specifically, DR preserved neuronal survival, maintained dendritic architecture and spine density, and reduced neuroinflammation in the hippocampus. These findings offer new insights into the etiology of SCA19/22-related symptoms and suggest that DR may serve as a potential therapeutic strategy targeting cognitive deficits in patients carrying the KCND3 F227del mutation.