The Precise Temporal Pattern of Prehearing Spontaneous Activity Is Necessary for Tonotopic Map Refinement

Abstract

SUMMARY Patterned spontaneous activity is a hallmark of developing sensory systems. In the auditory system, rhythmic bursts of spontaneous activity are generated in cochlear hair cells and propagated along central auditory pathways. The role of these activity patterns in the development of central auditory circuits has remained speculative. Here we demonstrate that blocking efferent cholinergic neurotransmission to developing hair cells in mice that lack the α9 subunit of nicotinic acetylcholine receptors (α9 KO mice) altered the temporal fine-structure of spontaneous activity without changing activity levels. KO mice showed a severe impairment in the functional and structural sharpening of an inhibitory tonotopic map, as evidenced by deficits in synaptic strengthening and silencing of connections and an absence in axonal pruning. These results provide evidence that the precise temporal pattern of spontaneous activity before hearing onset is crucial for the establishment of precise tonotopy, the major organizing principle of central auditory pathways.

Spontaneous activity in the developing auditory system

“…Indeed, subsequent studies revealed that SGNs exhibit a stereotyped firing pattern during this prehearing period, in which each burst is comprised of a series of mini-bursts, a reflection of the ability of each IHC Ca 2+ spike to induce repetitive firing of SGNs (Tritsch et al 2010a). This stereotyped firing pattern within bursts is also exhibited by neurons in the cochlear nucleus and the MNTB (Tritsch et al 2010a;Clause et al 2014), providing further support for the cochlear origin of this activity. Together, these experiments indicate that ATP is spontaneously released from ISCs in the prehearing cochlea, which activates purinergic receptors on IHCs (and ISCs), ultimately leading to bursts of action potentials in SGNs and auditory neurons of the brain (Fig.…”

“…Finally, this model predicts that removal of MOC cholinergic input would result in a conversion of auditory neuron activity from bursting to continuous firing. However, a recent study showed that MNTB neurons in vivo continue to fire in discrete bursts in mice that lack the α9 acetylcholine receptor subunit, which is required for MOC-mediated inhibition of IHCs (Vetter et al 1999;Clause et al 2014). Together, these results indicate that inhibitory input from MOC efferents is not essential to induce burst firing in auditory neurons, and suggest that there may be other extrinsic mechanisms to trigger periodic excitation of IHCs.…”

Re-Emergent Inhibition of Cochlear Inner Hair Cells in a Mouse Model of Hearing Loss

“…Calcium influx through these nAChRs gates associated small-conductance, calcium-activated potassium (SK) channels, rendering these synapses inhibitory (Glowatzki and Fuchs, 2000). The function of efferent innervation of immature IHCs is uncertain, but it is thought that efferent inhibition patterns the activity of the developing auditory pathway (Johnson et al, 2011) and plays a role in establishing central tonotopy (Clause et al, 2014;Sendin et al, 2014). After P14, IHCs lose their efferent contacts, nAChRs, and SK channels and are no longer responsive to ACh (Simmons, 2002;Katz et al, 2004).…”

L-type calcium channels in the auditory system

“…Via the unusual combination of postsynaptic α9/α10 acetylcholine receptors and the SK2 K + channel, acetylcholine, the neurotransmitter of cholinergic neurons, triggers inhibitory postsynaptic potentials, thus interrupting IHC activity [10]. This interplay between spontaneous IHC activity and medial olivocochlear efferent inhibition is essential for auditory pathway maturation before the onset of sensory experience [6]. In Ca v 1.3-deficient mice, expression of α9/α10 acetylcholine receptors and SK2 channels, whose occurrence in immature IHC is only of short duration, is not turned off.…”