Abstract
Neurons in developing sensory pathways exhibit spontaneous bursts of electrical activity that are critical for survival, maturation and circuit refinement. In the auditory system, intrinsically generated activity arises within the cochlea, but the molecular mechanisms that initiate this activity remain poorly understood. We show that burst firing of mouse inner hair cells prior to hearing onset requires P2RY1 autoreceptors expressed by inner supporting cells. P2RY1 activation triggers K+ efflux and depolarization of hair cells, as well as osmotic shrinkage of supporting cells that dramatically increased the extracellular space and speed of K+ redistribution. Pharmacological inhibition or genetic disruption of P2RY1 suppressed neuronal burst firing by reducing K+ release, but unexpectedly enhanced their tonic firing, as water resorption by supporting cells reduced the extracellular space, leading to K+ accumulation. These studies indicate that purinergic signaling in supporting cells regulates hair cell excitability by controlling the volume of the extracellular space.
Highlights
The developing nervous system must generate, organize, and refine billions of neurons and their connections
To define the signaling pathways engaged by purinergic receptor activation, we examined the sensitivity of spontaneous inner supporting cells (ISCs) whole-cell currents and crenations to inhibitors of intracellular
In the CNS, homeostatic control of extracellular K+ levels is accomplished by glial cells, which redistribute K+ passively through ion channels and actively through facilitated transport, but much less is known about the mechanisms that control excitability in the peripheral nervous system
Summary
The developing nervous system must generate, organize, and refine billions of neurons and their connections. Coincident with the refinement of topographic maps, nascent circuits experience bursts of intrinsically generated activity that emerge before sensory systems are fully functional (Kirkby et al, 2013). This intrinsically generated activity consists of periodic bursts of high frequency firing that promotes the survival and maturation of neurons in sensory pathways (Blankenship and Feller, 2010; Moody and Bosma, 2005). In all sensory systems that have been examined, spontaneous burst firing arises within their respective developing sensory organs, e.g. retina, olfactory bulb, spindle organ, and cochlea (Blankenship and Feller, 2010)
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