The voltage-gated Ca²⁺ channel subunit α₂δ-4 regulates locomotor behavior and sensorimotor gating in mice

Voltage-gated Ca²⁺ channels are critical for the development and mature function of the nervous system. Variants in the CACNA2D4 gene encoding the α₂δ-4 auxiliary subunit of these channels are associated with neuropsychiatric and neurodevelopmental disorders. α₂δ-4 is prominently expressed in the retina and is crucial for vision, but extra-retinal functions of α₂δ-4 have not been investigated. Here, we sought to fill this gap by analyzing the behavioral phenotypes of α₂δ-4 knockout (KO) mice. α₂δ-4 KO mice (both males and females) exhibited significant impairments in prepulse inhibition that were unlikely to result from the modestly elevated auditory brainstem response thresholds. Whereas α₂δ-4 KO mice of both sexes were hyperactive in various assays, only females showed impaired motor coordination in the rotarod assay. α₂δ-4 KO mice exhibited anxiolytic and anti-depressive behaviors in the elevated plus maze and tail suspension tests, respectively. Our results reveal an unexpected role for α₂δ-4 in sensorimotor gating and motor function and identify α₂δ-4 KO mice as a novel model for studying the pathophysiology associated with CACNA2D4 variants.