Purinergic signaling controls spontaneous activityin 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. SIGNIFICANCE STATEMENTIn developing sensory systems, groups of neurons that will process information from similar sensory space exhibit highly correlated electrical activity that is critical for proper maturation and circuit refinement. Defining the period when this activity is present, the mechanisms responsible and the features of this activity are crucial for understanding how spontaneous activity influences circuit development. We show that, from birth to hearing onset, the auditory system relies on a consistent mechanism to elicit correlate firing of neurons that will process similar frequencies of sound. Targeted disruption of this activity will increase our understanding of how these early circuits mature and may provide insight into processes responsible for developmental disorders of the auditory system.