The voltage-gated Cav Ca2+ channel subunit α2δ-4 is required for locomotor behavior and sensorimotor gating in mice

Voltage-gated Cav Ca2+ channels are critical for the development and mature function of the nervous system. Variants in the CACNA2D4 gene encoding the 2{delta}-4 auxiliary subunit of these channels are associated with neuropsychiatric and neurodevelopmental disorders. 2{delta}-4 is prominently expressed in the retina and is crucial for vision, but extra-retinal functions of 2{delta}-4 have not been investigated. Here, we sought to fill this gap by analyzing the behavioral phenotypes of 2{delta}-4 knockout (KO) mice. 2{delta}-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 2{delta}-4 KO mice of both sexes were hyperactive in various assays, only females showed impaired motor learning/coordination in the rotarod assay. Female but not male 2{delta}-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 2{delta}-4 in cognitive and motor function and identify 2{delta}-4 KO mice as a novel model for studying the pathophysiology associated with CACNA2D4 variants.