Purinergic signaling controls spontaneous activity in the auditory system throughout early development

Abstract

Spontaneous bursts of electrical activity in the developing auditory system arise within the cochlea prior to hearing onset and propagate through future sound processing circuits of the brain to promote maturation of auditory neurons. Studies in isolated cochleae revealed that this intrinsically generated activity is initiated by ATP release from inner supporting cells (ISCs), resulting in activation of purinergic autoreceptors, K+ efflux and subsequent depolarization of inner hair cells (IHCs). However, little is known about when this activity emerges or whether different mechanisms underlie distinct stages of development. Here we show that spontaneous electrical activity in mouse cochlea emerges within ISCs during the late embryonic period, preceding the onset of spontaneous correlated activity in IHCs and spiral ganglion neurons (SGNs), which begins at birth and follows a base to apex developmental gradient. At all developmental stages, pharmacological inhibition of P2Y1 metabotropic purinergic receptors dramatically reduced spontaneous activity in these three cell types. Moreover, in vivo imaging within the inferior colliculus of awake mice revealed that auditory neurons within future isofrequency zones exhibit coordinated neural activity at birth. The frequency of these discrete bursts increased progressively during the postnatal prehearing period, yet remained dependent on P2RY1. Analysis of mice with disrupted cholinergic signaling in the cochlea, indicate that this input modulates, rather than initiates, spontaneous activity before hearing onset. Thus, the auditory system uses a consistent mechanism involving ATP release from ISCs and activation of purinergic autoreceptors to elicit coordinated excitation of neurons that will process similar frequencies of sound.

Spontaneous activity in developing thalamic and cortical sensory networks

“…Apart from the activity mediated by supporting cells, IHCs have the intrinsic capacity to fire action potentials with different patterns along the baso-apical axis (Eckrich et al, 2018;Harrus et al, 2018;Johnson et al, 2011;Kros et al, 1998; but see Sendin et al, 2014). In turn, the electrical activity from IHCs excites primary sensory neurons (spiral ganglion neurons) that by P0 fire characteristic intermittent bursts of action potentials (Babola et al, 2020;Coate et al, 2019;Glowatzki and Fuchs, 2002;Zhang-Hooks et al, 2016).…”

“…The spatial activity in the inferior colliculus and auditory cortex in rodents has recently been studied by combining mesoscale calcium imaging with high spatial resolution two-photon microscopy. In the inferior colliculus, there are discrete, bilateral stationary bands of spontaneous activity oriented within prospective isofrequency domains (Babola et al, 2020). Bilateral bands are present as early as P1, and their frequency increases until P11-P12.…”

Spatial organization and transitions of spontaneous neuronal activities in the developing sensory cortex

“…ATP activates autoreceptors on the inner supporting cells (Babola et al., 2020; Tritsch & Bergles, 2010; Tritsch et al., 2007; Wang et al., 2015). Pharmacological inhibition or genetic deletion of purinergic receptors revealed that the supporting cell firing relies on the metabotropic purinergic receptors P2RY1 at least from birth to hearing onset (Babola, Li, et al., 2021). The activation of P2RY1 receptors of the inner supporting cells induces the release of K + from these cells.…”

Using light-sheet microscopy to study spontaneous activity in the developing lateral-line system

“…In the mammalian auditory system, extracellular ATP and P2 purinergic signaling is required for spontaneous activity in supporting cells (Babola et al, 2020;Babola et al, 2021). Previous work has shown that pharmacological block of P2RY1 receptors and downstream phospholipase C-β (PLC-β) signaling components blocked spontaneous activity in supporting cells (Babola et al, 2020).…”

“…For coordinated waves of activity among hair cells, concurrent waves of calcium propagate through glia-like supporting cells that surround or are adjacent to hair cells. In cochlear supporting cells, this activity is dependent on ATP and purinergic signaling and propagates via gap junction channels between supporting cells (Tritsch et al, 2007;Ceriani et al, 2019;Babola et al, 2021). Ultimately, ATP signaling in supporting cells drives spontaneous activity in nearby auditory hair cells.…”