Homeostatic Control of Spontaneous Activity in the Developing Auditory System

Abstract

Neurons in the developing auditory system exhibit spontaneous bursts of activity before hearing onset. How this intrinsically generated activity influences development remains uncertain, because few mechanistic studies have been performed in vivo. We show using macroscopic calcium imaging in unanesthetized mice that neurons responsible for processing similar frequencies of sound exhibit highly synchronized activity throughout the auditory system during this critical phase of development. Spontaneous activity normally requires synaptic excitation of spiral ganglion neurons (SGNs). Unexpectedly, tonotopic spontaneous activity was preserved in a mouse model of deafness in which glutamate release from hair cells is abolished. SGNs in these mice exhibited enhanced excitability, enabling direct neuronal excitation by supporting cell-induced potassium transients. These results indicate that homeostatic mechanisms maintain spontaneous activity in the pre-hearing period, with significant implications for both circuit development and therapeutic approaches aimed at treating congenital forms of deafness arising through mutations in key sensory transduction components.

Topographic map refinement and synaptic strengthening of a sound localization circuit require spontaneous peripheral activity

“…; Babola et al . ). Because transmitter release from IHCs is decreased by ∼90% in Otof KOs (Heidrych et al .…”

“…; Babola et al . ). Therefore, IHCs appear to be peripheral pacemakers for central targets during prehearing development (Blankenship & Feller, ).…”

“…Furthermore, the frequency of spontaneous activity in Slc17a8 KOs is compensated by hyperexcitable spiral ganglion neurons that are directly depolarized and forced to generate spikes by K + release from inner supporting cells, therefore bypassing abolished glutamate release from IHCs (Babola et al . ; Sun et al . ).…”

“…; Babola et al . ), and the feature is highly conserved across species (Wang & Bergles, ). The spontaneous activity arises from immature IHCs, which fire Ca 2+ action potentials and release glutamate (Kros et al .…”

“…Mice are sensory altricial and physiologically deaf until ßP12, when hearing onset occurs (Mikaelian & Ruben, 1965;Ehret, 1976Ehret, , 1983. Remarkably, spontaneous activity propagates through the auditory system in prehearing animals (Tritsch et al 2007;Sonntag et al 2009;Babola et al 2018), and the feature is highly conserved across species (Wang & Bergles, 2015). The spontaneous activity arises from immature IHCs, which fire Ca 2+ action potentials and release glutamate (Kros et al 1998;Tritsch et al 2010;Johnson et al 2012;Sendin et al 2014;Eckrich et al 2018).…”