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J Neurosci. 2019 Jul 3;39(27):5284-5298. doi: 10.1523/JNEUROSCI.2728-18.2019. Epub 2019 May 13.

Pou4f1 Defines a Subgroup of Type I Spiral Ganglion Neurons and Is Necessary for Normal Inner Hair Cell Presynaptic Ca2+ Signaling.

Author information

1
Laboratory of Cochlear Development, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892.
2
Department of Neuroscience and Brown Institute for Brain Science, Brown University, Providence, Rhode Island 02912.
3
Institute for Auditory Neuroscience and Inner Ear Laboratory, University Medical Center Göttingen, 37073 Göttingen, Germany.
4
Göttingen Graduate School for Neurosciences and Molecular Biosciences, University of Göttingen, 37073 Göttingen, Germany.
5
Auditory Neuroscience Group, Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany.
6
Mouse Auditory Testing Core Facility, National Institute on Deafness and Other Communication Disorders, Bethesda, Maryland 20892, and.
7
Institute for Auditory Neuroscience and Inner Ear Laboratory, University Medical Center Göttingen, 37073 Göttingen, Germany, kelleymt@nidcd.nih.gov tmoser@gwdg.de.
8
Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University of Göttingen, 37075 Göttingen, Germany.
9
Laboratory of Cochlear Development, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, kelleymt@nidcd.nih.gov tmoser@gwdg.de.

Abstract

Acoustic signals are relayed from the ear to the brain via spiral ganglion neurons (SGNs) that receive auditory information from the cochlear inner hair cells (IHCs) and transmit that information to the cochlear nucleus of the brainstem. Physiologically distinct classes of SGNs have been characterized by their spontaneous firing rate and responses to sound and those physiological distinctions are thought to correspond to stereotyped synaptic positions on the IHC. More recently, single-cell profiling has identified multiple groups of SGNs based on transcriptional profiling; however, correlations between any of these groups and distinct neuronal physiology have not been determined. In this study, we show that expression of the POU (Pit-Oct-Unc) transcription factor Pou4f1 in type I SGNs in mice of both sexes correlates with a synaptic location on the modiolar side of IHCs. Conditional deletion of Pou4f1 in SGNs beginning in mice at embryonic day 13 rescues the early path-finding and apoptotic phenotypes reported for germline deletion of Pou4f1, resulting in a phenotypically normal development of SGN patterning. However, conditional deletion of Pou4f1 in SGNs alters the activation of Ca2+ channels in IHCs primarily by increasing their voltage sensitivity. Moreover, the modiolar to pillar gradient of active zone Ca2+ influx strength is eliminated. These results demonstrate that a subset of modiolar-targeted SGNs retain expression of Pou4f1 beyond the onset of hearing and suggest that this transcription factor plays an instructive role in presynaptic Ca2+ signaling in IHCs.SIGNIFICANCE STATEMENT Physiologically distinct classes of type I spiral ganglion neurons (SGNs) are necessary to encode sound intensities spanning the audible range. Although anatomical studies have demonstrated structural correlates for some physiologically defined classes of type I SGNs, an understanding of the molecular pathways that specify each type is only now emerging. Here, we demonstrate that expression of the transcription factor Pou4f1 corresponds to a distinct subgroup of type I SGNs that synapse on the modiolar side of inner hair cells. The conditional deletion of Pou4f1 after SGN formation does not disrupt ganglion size or morphology, change the distribution of IHC synaptic locations, or affect the creation of synapses, but it does influence the voltage dependence and strength of Ca2+ influx at presynaptic active zones in inner hair cells.

KEYWORDS:

cochlea; ear; hearing; synaptogenesis

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