Coordinated calcium signalling in cochlear sensory and non‐sensory cells refines afferent innervation of outer hair cells

• Published in: The EMBO journal 2019-05, Vol.38 (9), p.n/a
• Main Authors: Ceriani, Federico, Hendry, Aenea, Jeng, Jing‐Yi, Johnson, Stuart L, Stephani, Friederike, Olt, Jennifer, Holley, Matthew C, Mammano, Fabio, Engel, Jutta, Kros, Corné J, Simmons, Dwayne D, Marcotti, Walter
• Format: Article
• Language: English
• Subjects: Action Potentials; Activation; Afferent Pathways; Animals; ATP; Calcium; Calcium (extracellular); Calcium - metabolism; Calcium channels; Calcium Channels, L-Type - physiology; Calcium ions; Calcium Signaling; Calcium signalling; calcium waves; Cochlea; Cochlea - physiology; Connexin 30 - physiology; EMBO11; EMBO20; Fibers; Hair; Hair cells; Hair Cells, Auditory, Outer - physiology; Innervation; Mammals; Mice; Mice, Knockout; Mice, Transgenic; Neonates; Neural networks; Outer hair cells; pre‐hearing development; purinergic receptors; Receptors; Receptors, Purinergic P2X3 - physiology; Sensory neurons; Sensory Receptor Cells - physiology; spontaneous activity; Synapses; Synapses - physiology; Synaptic ribbons; Synchronism; Synchronization
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201899839

Outer hair cells (OHCs) are highly specialized sensory cells conferring the fine‐tuning and high sensitivity of the mammalian cochlea to acoustic stimuli. Here, by genetically manipulating spontaneous Ca 2+ signalling in mice in vivo, through a period of early postnatal development, we find that the refinement of OHC afferent innervation is regulated by complementary spontaneous Ca 2+ signals originating in OHCs and non‐sensory cells. OHCs fire spontaneous Ca 2+ action potentials during a narrow period of neonatal development. Simultaneously, waves of Ca 2+ activity in the non‐sensory cells of the greater epithelial ridge cause, via ATP‐induced activation of P2X 3 receptors, the increase and synchronization of the Ca 2+ activity in nearby OHCs. This synchronization is required for the refinement of their immature afferent innervation. In the absence of connexin channels, Ca 2+ waves are impaired, leading to a reduction in the number of ribbon synapses and afferent fibres on OHCs. We propose that the correct maturation of the afferent connectivity of OHCs requires experience‐independent Ca 2+ signals from sensory and non‐sensory cells. Synopsis How Ca 2+ ‐dependent activities guide the early development of specialized outer hair cells and their afferent neuronal connectivity is poorly understood. Spontaneous Ca 2+ waves in non‐sensory cells increase and synchronize Ca 2+ signalling in outer hair cells are now found to promote functional differentiation and innervation of sensory cells. Immature outer hair cells (OHCs) spontaneously show transient Ca 2+ signals at around birth in mice. Calcium waves in non‐sensory cells are able to increase and synchronise Ca 2+ signals in OHCs. The extracellular modulation of OHC Ca 2+ signalling activity requires ATP and activation of P2X 3 receptors in OHCs. Loss of Ca 2+ waves in cochlear non‐sensory cells prevents the acquisition of the normal innervation pattern of OHCs. Graphical Abstract Spontaneous Ca 2+ waves in non‐sensory cells increase and synchronize Ca 2+ signalling in outer hair cells via ATP‐induced activation of P2X 3 receptors, promoting functional differentiation and innervation of sensory cells.