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 ␣ 2 ␦3 modulates the expression and function of voltage-gated calcium channels. Here we show that ␣ 2 ␦3 mRNA is expressed in spiral ganglion neurons and auditory brainstem nuclei and that the protein is required for normal acoustic responses. Genetic deletion of ␣ 2 ␦3 led to impaired auditory processing, with reduced acoustic startle and distorted auditory brainstem responses. ␣ 2 ␦3 Ϫ/Ϫ 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 Ca 2ϩ channels and smaller auditory nerve fiber terminals contacting cochlear nucleus bushy cells. Juxtacellular in vivo recordings of sound-evoked activity in ␣ 2 ␦3 Ϫ/Ϫ mice demonstrated impaired transmission at these synapses. Together, our results identify a novel role for the ␣ 2 ␦3 auxiliary subunit in the structure and function of specific synapses in the mammalian auditory pathway and in auditory processing disorders.

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…The a 2 d subunits have a similar domain structure to many proteins involved in extracellular matrix and extracellular protein-protein interactions (Whittaker and Hynes, 2002). Indeed, a 2 d-1 has been reported to interact with thrombospondins and to have a structural role in synapse formation (Eroglu et al, 2009), and the a 2 d proteins in Drosophila have been shown to have an effect on presynaptic morphology (Dickman et al, 2008;Kurshan et al, 2009), as is also the case for a 2 d-3 in an auditory system synapse (Pirone et al, 2014). Since a 2 d subunits are involved in calcium channel trafficking as well as function, it may be difficult to tease apart their roles independent of calcium channels.…”

“…For the Ca V 1.1 channel complex in skeletal muscle, a 2 d-1 was also found to have a functional role in excitation-coupled entry of Ca 2+ into skeletal myotubes, although not in the formation of the Ca V 1.1 tetrad structure or in excitation-contraction coupling (Obermair et al, 2005;Gach et al, 2008). In mice in which a 2 d subunits were depleted, there was a reduction of calcium currents in relevant cell types (Barclay et al, 2001;Fuller-Bicer et al, 2009;Patel et al, 2013;Pirone et al, 2014).…”

“…Hearing. A role for a 2 d-3 in hearing has been identified using a knockout mouse for a 2 d-3 (Pirone et al, 2014). This study identified reduced presynaptic Ca 2+ channels and smaller auditory nerve fiber terminals synapsing on cochlear nucleus bushy cells to be associated with a specific hearing impairment resulting from the loss of a 2 d-3.…”

The Auxiliary Calcium Channel Subunit α2δ4 Is Required for Axonal Elaboration, Synaptic Transmission, and Wiring of Rod Photoreceptors

“…These observations may suggest a general mechanism by which α2δ proteins exert synaptogenenic effects. For instance, loss of α2δ3 function has been shown to result in deficits in synapse formation and a decrease of synaptic transmission (Hoppa et al, 2012; Pirone et al, 2014), whereas overexpression of α2δ1 was reported to increase assembly of functional synapses working in concert with extracellular matrix protein thrombospondin 1 (Eroglu et al, 2009) and α2δ3 in hair cells was shown to control trans -synaptically AMPA receptor recruitment (Fell et al, 2016). Despite these advances, the molecular mechanisms that mediate the effects of α2δ proteins on synapse formation were not elucidated.…”

Temporal Lobe Epilepsy, Stroke, and Traumatic Brain Injury: Mechanisms of Hyperpolarized, Depolarized, and Flow-Through Ion Channels Utilized as Tri-Coordinate Biomarkers of Electrophysiologic Dysfunction

“…These channels are closely related to the CaV3 channel, which also has an alpha unit pore [56]. Splicing variants of each subunit contribute to altered phenotypes associated with epilepsy [57]. These splice variants determine biophysical properties and tissue location of channels [58].…”