A critical period of prehearing spontaneous Ca2+ spiking is required for hair-bundle maintenance in inner hair cells

 Back to publications


EMBO J. 2023 Feb 15;42(4):e112118. doi: 10.15252/embj.2022112118. Epub 2023 Jan 3.

A critical period of prehearing spontaneous Ca2+ spiking is required for hair-bundle maintenance in inner hair cells

Adam J Carlton, Jing-Yi Jeng, Fiorella C Grandi, Francesca De Faveri, Federico Ceriani, Lara De Tomasi, Anna Underhill, Stuart L Johnson, Kevin P Legan, Corné J Kros, Guy P Richardson, Mirna Mustapha, Walter Marcotti

School of Biosciences, University of Sheffield, Sheffield, UK. Gladstone Institute of Neurological Disease, San Francisco, CA, USA. Neuroscience Institute, University of Sheffield, Sheffield, UK. School of Life Sciences, University of Sussex, Falmer, Brighton, UK.

Service type: Knock-in mice


Sensory-independent Ca2+ spiking regulates the development of mammalian sensory systems. In the immature cochlea, inner hair cells (IHCs) fire spontaneous Ca2+ action potentials (APs) that are generated either intrinsically or by intercellular Ca2+ waves in the nonsensory cells. The extent to which either or both of these Ca2+ signalling mechansims are required for IHC maturation is unknown. We find that intrinsic Ca2+ APs in IHCs, but not those elicited by Ca2+ waves, regulate the maturation and maintenance of the stereociliary hair bundles. Using a mouse model in which the potassium channel Kir2.1 is reversibly overexpressed in IHCs (Kir2.1-OE), we find that IHC membrane hyperpolarization prevents IHCs from generating intrinsic Ca2+ APs but not APs induced by Ca2+ waves. Absence of intrinsic Ca2+ APs leads to the loss of mechanoelectrical transduction in IHCs prior to hearing onset due to progressive loss or fusion of stereocilia. RNA-sequencing data show that pathways involved in morphogenesis, actin filament-based processes, and Rho-GTPase signaling are upregulated in Kir2.1-OE mice. By manipulating in vivo expression of Kir2.1 channels, we identify a "critical time period" during which intrinsic Ca2+ APs in IHCs regulate hair-bundle function.

Keywords: calcium waves; development; hair cell; mechanoelectrical transduction; spontaneous action potentials.

View Publication