Abstract
Before hearing onset (postnatal day 12 in mice), inner hair cells (IHCs) 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 (ISCs) 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. These results reveal the importance of the activity of Kölliker's organ for the refinement of central auditory connectivity. In addition, our study suggests the involvement of TMEM16A in the propagation of Ca2+ waves, which may also apply to other tissues expressing TMEM16A.
Highlights
MethodsKey Resources TableReagent type (species) or resourceDesignation gene (mouse)Ano (Tmem16a) strain, strain background (Mus musculus)Ano1fl/fl strain, strain background (Mus musculus) Ano KOPax2Cre strain, strain background (Mus musculus)C57BL6/J antibody anti-TMEM16A polyclonal rabbit antibody anti-TMEM16B polyclonal rabbit antibody antibody anti-CD31 monoclonal ratAlexa Fluor 488, polyclonal goat anti rabbitSource or referenceGenBank published in Heinze et al, 2013 published in Billig et al, 2011 published in Ohyama & Groves, 2004
It was proposed that the Ca2+-activated Cl--channel TMEM16A, which is expressed in inner supporting cells (ISC), might be the pacemaker for spontaneous cochlear activity (Yi et al, 2013)
78 spontaneous osmotic cell shrinkage was shown to be mediated by TMEM16A-dependent Cl79 efflux, which forces K+ efflux from ISCs and the transient depolarization of inner hair cells (IHC) (Yi et al, 80 2013)
Summary
Key Resources TableReagent type (species) or resourceDesignation gene (mouse)Ano (Tmem16a) strain, strain background (Mus musculus)Ano1fl/fl strain, strain background (Mus musculus) Ano KOPax2Cre strain, strain background (Mus musculus)C57BL6/J antibody anti-TMEM16A polyclonal rabbit antibody anti-TMEM16B polyclonal rabbit antibody antibody anti-CD31 monoclonal ratAlexa Fluor 488, polyclonal goat anti rabbitSource or referenceGenBank published in Heinze et al, 2013 published in Billig et al, 2011 published in Ohyama & Groves, 2004. Ano (Tmem16a) strain, strain background (Mus musculus). Ano1fl/fl strain, strain background (Mus musculus) Ano KO. C57BL6/J antibody anti-TMEM16A polyclonal rabbit antibody anti-TMEM16B polyclonal rabbit antibody antibody anti-CD31 monoclonal rat. Alexa Fluor 488, polyclonal goat anti rabbit. GenBank published in Heinze et al, 2013 published in Billig et al, 2011 published in Ohyama & Groves, 2004
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