Compartmentalization of antagonistic Ca ²⁺ signals in developing cochlear hair cells

Abstract

During a critical developmental period, cochlear inner hair cells (IHCs) exhibit sensory-independent activity, featuring action potentials in which Ca ions play a fundamental role in driving both spiking and glutamate release onto synapses with afferent auditory neurons. This spontaneous activity is controlled by a cholinergic input to the IHC, activating a specialized nicotinic receptor with high Ca permeability, and coupled to the activation of hyperpolarizing SK channels. The mechanisms underlying distinct excitatory and inhibitory Ca roles within a small, compact IHC are unknown. Making use of Ca imaging, afferent auditory bouton recordings, and electron microscopy, the present work shows that unusually high intracellular Ca buffering and "subsynaptic" cisterns provide efficient compartmentalization and tight control of cholinergic Ca signals. Thus, synaptic efferent Ca spillover and cross-talk are prevented, and the cholinergic input preserves its inhibitory signature to ensure normal development of the auditory system.

Strengthening of the efferent olivocochlear system leads to synaptic dysfunction and tonotopy disruption of a central auditory nucleus

“…The results shown in the present study clearly indicate that the transient α9α10-mediated transmission to IHCs is crucial for modulating spiking-dependent development of the auditory system. Since during development a modest stimulation rate of efferent fibers is sufficient to produce strong, near-maximal inhibition of IHC firing (Moglie et al, 2018), and this inhibition is exacerbated in the L9’T mutant mice (Wedemeyer et al, 2018), the resultant phenotype most likely results from the silencing of IHC spiking activity.…”

“…Exogenously applied acetylcholine (Glowatzki and Fuchs, 2000) or electrical stimulation of efferent terminals (Goutman et al, 2005; Wedemeyer et al, 2018) inhibits IHC action potentials. Therefore, it has been proposed that cholinergic efferent inhibition of IHCs might impose rhythmicity onto IHC action potential generation and spontaneous activity of the auditory pathway during the critical developmental period preceding hearing onset (Glowatzki and Fuchs, 2000; Johnson et al, 2011; Sendin et al, 2014; Moglie et al, 2018). However, this notion has been challenged (Tritsch et al, 2010a), and therefore the function of the developmental efferent innervation is still a matter of debate.…”

Developmental synaptic changes at the transient olivocochlear-inner hair cell synapse

“…The position of the pipette was adjusted until postsynaptic currents obtained by voltage-clamping the IHC in the whole-cell configuration were consistently activated. The only data on the number of MOC-IHC functional synaptic contacts at the MOC-IHC transient synapse is that found in Moglie et al (2018). By doing minimal-maximal electrical stimulation of the efferent fibers in mice at P9 -P11, they report at most 2-8 (average 5.9) MOC-IHC synaptic contacts per IHC, which can be sequentially activated upon increasing the stimulus strength.…”

“…However, during postnatal development, before the onset of hearing at postnatal day 12 (P12) in altricial rodents, MOC fibers transiently innervate the IHCs (Glowatzki and Fuchs, 2000;Katz et al, 2004;Roux et al, 2011) even before contacting their final targets, the OHCs (Liberman et al, 1990;Simmons et al, 1996;Simmons, 2002). Several studies suggest that this transient efferent innervation plays a role in the ultimate functional maturation of cochlear hair cells (Simmons, 2002) and in the correct establishment of the auditory pathway by regulating the spontaneous IHC firing frequency during this critical developmental period (Glowatzki and Fuchs, 2000;Goutman et al, 2005;Johnson et al, 2013;Sendin et al, 2014;Moglie et al, 2018;Wedemeyer et al, 2018). This notion is reinforced by the observation that mice that lack functional efferent MOC-hair cell synapses present a decreased tonotopic organization in the lateral superior olive and a concomitant impairment in the detection of sound frequency changes (Clause et al, 2014(Clause et al, , 2017.…”

Strengthening of the Efferent Olivocochlear System Leads to Synaptic Dysfunction and Tonotopy Disruption of a Central Auditory Nucleus

“…Exogenously applied acetylcholine (Glowatzki and Fuchs, 2000) or electrical stimulation of the efferent terminals (Goutman et al, 2005;Wedemeyer et al, 2018) inhibits IHC APs. Therefore, it has been proposed that cholinergic efferent inhibition of IHCs might impose rhythmicity to the generation of IHC APs and the spontaneous activity of the auditory pathway during the critical period preceding hearing onset (Glowatzki and Fuchs, 2000;Johnson et al, 2011;Sendin et al, 2014;Moglie et al, 2018). However, this notion has been challenged ; therefore, the function of the developmental efferent innervation is still a matter of debate.…”