Role of voltage-gated calcium channel alpha2delta subunits for spiral ganglion neurons and afferent auditory processing

• Applicant: Professorin Dr. Jutta Engel, since 9/2016
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cognitive, Systems and Behavioural Neurobiology
• Term: from 2012 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 217904001

Hair cells and neurons of the auditory pathway use distinct ion channels, transmitter receptors and synapse specializations to guarantee ultrafast signalling with exquisitely high temporal precision. This also applies to voltage-gated Ca2+ channels (VGCC), which are required for presynaptic Ca2+ influx and transmitter release. VGCCs are multimeric protein complexes consisting of a pore-forming alpha1 subunit, an intracellular beta-subunit and an extracellular alpha2delta (a2d) subunit. Biophysical and pharmacological properties are largely determined by one of the ten alpha1 subunits, whereas beta and a2d subunits assist in surface expression of VGCCs and fine-tune channel gating. Four different a2d subunits exist with partially redundant and partially specific functions. We have previously shown that a2d3-deficient mice have distorted auditory evoked brainstem responses despite only mildly elevated hearing thresholds and normal physiology and morphology of hair cells. Lack of a2d3 reduced somatic Ca2+ currents of cultured spiral ganglion neurons (SGN). Synaptic transmission from auditory nerve fibers to bushy cells of the cochlear nucleus was compromised, and sizes of auditory nerve fiber terminals were markedly reduced. Moreover, the mice were unable to discriminate amplitude-modulated tones in a behavioral task, establishing the a2d3-deficient mouse as model for an auditory processing disorder. Because a2d3 is expressed beyond SGN in several nuclei of the afferent auditory pathway, we will dissect the specific roles of a2d3 by analysing a conditional mouse model that specifically lacks a2d3 in SGN with (a) Ca2+ current recordings, (b) in-vivo recordings of neurons in the inferior colliculus and (c) auditory discrimination learning experiments. Evidence is accumulating that a2d subunits play additional roles than merely modulating Ca2+ flux through VGCCs, e.g. for the structure and function of pre- and postsynapses. Because SGN express mRNA for a2d1 and a2d2 as well, we will study the roles of these a2d subunits for SGN Ca2+ currents, Ca2+ channel protein expression and synapse morphology using a2d1 knockout and a2d2 mutant mice. In vivo recordings of neurons in the inferior colliculus will give insights into the ability of the different mice to process temporal information. Finally, behavioral auditory discrimination learning experiments will complement the picture of the role of a2d subunits in auditory processing.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1608: Ultrafast and Temporally Precise Information Processing: Normal and Dysfunctional Hearing
• Ehemalige Antragstellerin: Privatdozentin Dr. Simone Kurt, until 9/2016