Triggered Calcium Lightning Programs Cochlear Development

Spontaneous calcium (Ca²⁺) waves play a critical role as internal stimuli in the early developing auditory system before the onset of sensory experiences. However, neither the spatiotemporal control of spontaneous Ca²⁺ waves nor their impacts on auditory development are well understood. Here we report that a lateral array of inner supporting cells (ISCs) beneath the inner hair cells displays a spontaneous ultra-long, ultra-fast, transient Ca²⁺ flash, termed "Ca²⁺ lightning", which triggers a series of simultaneous bursts of Ca²⁺ waves in the whole cochlea, before the ear canal opening. The Ca²⁺ lightning margins the cochlear ISCs at different developmental stages that correspondingly exhibit different Ca²⁺ activities. Triggered by an ATP-induced high-level Ca²⁺ wave, the Ca²⁺ lightning rapidly propagates laterally into neighboring ISCs through the intricate interplay of the T-type Ca²⁺ channel, Anoctamin 1 (Ano1) Ca²⁺-activated Cl^- channel and Connexin 26 (Cx26). The genetic deletion of Cav3.2, Ano1, or Cx26 abrogates Ca²⁺ lightning flashes and dysregulates cell development and functions in peripheral cochleae. We propose that cochlear Ca²⁺ lightning flashes orderly with Ca²⁺ waves together orchestrate the spatiotemporal maturation processes of the peripheral auditory system before the onset of hearing.