The Cl--channel TMEM16A is involved in the generation of cochlear Ca2+ waves and promotes the refinement of auditory brainstem networks in mice

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Abstract

Before hearing onset (postnatal day 12 in mice), inner hair cells (IHC) spontaneously fire action potentials thereby driving pre-sensory activity in the ascending auditory pathway. The rate of IHC action potential bursts is modulated by inner supporting cells (ISC) of Kölliker's organ through the activity of the Ca²⁺ activated Cl^- channel TMEM16A (ANO1). Here we show that conditional deletion of Ano1 (Tmem16a) in mice disrupts Ca²⁺ waves within Kölliker's organ, reduces the burst firing activity and the frequency-selectivity of auditory brainstem neurons in the medial nucleus of the trapezoid body (MNTB), and also impairs the functional refinement of MNTB projections to the lateral superior olive (LSO). These results reveal the importance of the activity of Kölliker's organ for the refinement of central auditory connectivity. In addition, our study suggests involvement of TMEM16A in the propagation of Ca²⁺ waves, which may also apply to other tissues expressing TMEM16A.

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All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided and did not change for the revised manuscript.

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Alena Maul

Neuroscience Department, Max Delbrück Center for Molecular Medicine, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Antje Kathrin Huebner

Institute of Human Genetics, University Hospital Jena, Jena, Germany

Competing interests
The authors declare that no competing interests exist.
Nicola Strenzke

Institute for Auditory Neuroscience, Department of Otolaryngology, University of Göttingen, Göttingen, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1673-1046
Tobias Moser

Institute for Auditory Neuroscience, Department of Otolaryngology, University of Göttingen, Göttingen, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7145-0533
Rudolf Rübsamen

Faculty of Bioscience, Pharmacy and Psychology, University of Leipzig, Leipzig, Germany

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The authors declare that no competing interests exist.
Saša Jovanovic

Faculty of Bioscience, Pharmacy and Psychology, University of Leipzig, Leipzig, Germany

Competing interests
The authors declare that no competing interests exist.
Christian A Hübner

Institute of Human Genetics, University Hospital Jena, Jena, Germany

For correspondence
christian.huebner@med.uni-jena.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1030-4943

Funding

Deutsche Forschungsgemeinschaft (HU 800/10-1)

Christian A Hübner

Deutsche Forschungsgemeinschaft (priority program 1608)

Nicola Strenzke
Tobias Moser
Rudolf Rübsamen

Bundesministerium für Bildung und Forschung (01EW1706)

Christian A Hübner

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to our local authorities (license numbers: 33.9-42502-04-11/0439; TVV 06/09 and TLV UKJ-17-006).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.