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 alpha(2)delta-4 auxiliary subunit of these channels are associated with neuropsychiatric and neurodevelopmental disorders. alpha(2)delta-4 is prominently expressed in the retina and is crucial for vision, but extra-retinal functions of alpha(2)delta-4 have not been investigated. Here, we sought to fill this gap by analyzing the behavioral phenotypes of alpha(2)delta-4 knockout (KO) mice. alpha(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 alpha(2)delta-4 KO mice of both sexes were hyperactive in various assays, only females showed impaired motor coordination in the rotarod assay. alpha(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 alpha(2)delta-4 in sensorimotor gating and motor function and identify alpha(2)delta-4 KO mice as a novel model for studying the pathophysiology associated with CACNA2D4 variants.

Automated summary

Voltage-gated Ca2+ channels play a critical role in the development and function of the nervous system. Mutations in the CACNA2D4 gene, which encodes the alpha(2)delta-4 auxiliary subunit of these channels, are associated with neuropsychiatric and neurodevelopmental disorders. This study investigates the behavioral phenotypes of alpha(2)delta-4 knockout mice and reveals unexpected roles of alpha(2)delta-4 in sensorimotor gating and motor function.