α₂δ3 Is Essential for Normal Structure and Function of Auditory Nerve Synapses and Is a Novel Candidate for Auditory Processing Disorders

Abstract

The auxiliary subunit α₂δ3 modulates the expression and function of voltage-gated calcium channels. Here we show that α₂δ3 mRNA is expressed in spiral ganglion neurons and auditory brainstem nuclei and that the protein is required for normal acoustic responses. Genetic deletion of α₂δ3 led to impaired auditory processing, with reduced acoustic startle and distorted auditory brainstem responses. α₂δ3^−/− mice learned to discriminate pure tones, but they failed to discriminate temporally structured amplitude-modulated tones. Light and electron microscopy analyses revealed reduced levels of presynaptic Ca²⁺ channels and smaller auditory nerve fiber terminals contacting cochlear nucleus bushy cells. Juxtacellular in vivo recordings of sound-evoked activity in α₂δ3^−/− mice demonstrated impaired transmission at these synapses. Together, our results identify a novel role for the α₂δ3 auxiliary subunit in the structure and function of specific synapses in the mammalian auditory pathway and in auditory processing disorders.