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date: 26 May 2019

Efferent Innervation to the Cochlea

Abstract and Keywords

The auditory system consists of ascending and descending neuronal pathways. The best studied is the ascending pathway, whereby sounds that are transduced in the cochlea into electrical signals are sent to the brain via the auditory nerve. Before reaching the auditory cortex, auditory ascending information has several central relays: the cochlear nucleus and superior olivary complex in the brainstem, the lateral lemniscal nuclei and inferior colliculus in the midbrain, and the medial geniculate body in the thalamus. The function(s) of the descending corticofugal pathway is less well understood. It plays important roles in shaping or even creating the response properties of central auditory neurons and in the plasticity of the auditory system, such as reorganizing cochleotopic and computational maps. Corticofugal projections are present at different relays of the auditory system. This review focuses on the physiology and plasticity of the medial efferent olivocochlear system.

Keywords: olivocochlear, nicotinic receptors, ligand-gated channels, cochlea, critical period

Anatomy of the Olivocochlear Efferent Innervation

Rasmussen (1946) was the first one to provide a subdivision of the efferent pathway into uncrossed and crossed olivocochlear bundles, the latter crossing the midline near the floor of the fourth ventricle. Nowadays, olivocochlear efferents are subdivided into medial (MOC) and lateral (LOC), based on tract-tracing experiments (Brown, 1987; Warr, 1992; Warr, 1975); (Figure 1). Thin, unmyelinated lateral LOC efferents originate from small neurons in or around the lateral superior olivary nucleus and project through the vestibular nerve mainly to the region near inner hair cells (IHCs) in the ipsilateral cochlea. They form synaptic contacts on the radial dendrites of Type I auditory afferent fibers postsynaptic to the IHCs. Thick, myelinated MOC efferents originate from larger neurons located in the medial part of the superior olivary nucleus and project through the vestibular nerve mostly contralaterally to make synaptic contacts directly onto outer hair cells (OHCs; Figure 2). Both MOC and LOC efferent fibers also send collaterals to brainstem vestibular nuclei and the cochlear nucleus. Lateral and medial efferent innervation patterns differ along the length of the cochlea. LOC inputs spread widely throughout the cochlea (Maison, Adams, & Liberman, 2003; Vetter, Adams, & Mugnani, 1991). In contrast, MOC fibers peaks near the middle of the cochlear spiral with significantly lower innervation densities toward the basal and apical extremes (Maison et al., 2003). Most efferent effects studied to date are mainly attributed to the MOC system (Guinan, 1996). This derives from the fact that experimental approaches involve the electrical stimulation of efferent fibers at the floor of the fourth ventricle where MOC fibers are more exposed. In addition, medial efferents are myelinated and thus have a lower threshold for extracellular current stimulation than do the smaller unmyelinated LOC fibers. MOC and LOC neurons receive auditory innervation and are the final arms of acoustic reflexes. The MOC acoustic reflex is the best understood and has both an ipsilateral and contralateral arm with a relay in reflex interneurons in the posteroventral cochlear nuclei (de Venecia, Liberman, Guinan, & Brown, 2005; Figure 1).

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Figure 1. The olivocochlear reflex

Illustration of a transverse section of the brainstem; lateral olivocochlear (LOC, green) and medial olivocochlear (MOC, blue or red) neurons. The pathways for the ipsilateral and contralateral MOC reflexes to the right ear are shown in blue and red, respectively, and in gold when they join the olivocochlear bundle (OCB). Crossed (COCB) and uncrossed OCB (UOCB) components, are formed by LOC and MOC axons. CN, cochlear nucleus. The S-shaped gray structure is the lateral superior olivary nucleus, and the gray structure medial to it, is the medial superior olivary nucleus.

(Reproduced from Guinan, 2006.)

Efferent innervation to the cochlea undergoes extensive developmental remodeling. These descending fibers can be detected in the peripheral sensory epithelium around embryonic day 13 in rodents (Bruce, Kingsley, Nichols, & Fritzsch, 1997). MOC efferents transiently project to the IHC area during development, where they make direct axo-somatic contacts (Simmons, 2002). No direct contacts are seen over IHCs around the onset of hearing (P12 in altricial rodents), and only the LOC fibers make axo-dendritic synapses with afferent fibers in the IHC area in adults (Simmons, 2002). Efferents start to appear beneath the OHCs by P2 and to establish the adult-like axo-somatic synaptic contacts by P12 in altricial rodents (Bruce, Christensen, & Warr, 2000; Bruce et al., 1997; Bulankina & Moser, 2012; Rontal & Echteler, 2003; Simmons, 2002). (See Figure 2.). This developmental period where efferent fibers make direct contacts with IHCs is known as the “critical period” and appears to be important for the development of the auditory pathway (Clause et al., 2014; Clause, Lauer, & Kandler, 2017).

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Figure 2. Innervation of hair cells during development

Before the onset of hearing, the basal pole of cochlear inner hair cells (IHCs) is surrounded by immature afferent axosomatic, transient efferent axosomatic, and efferent axodendritic terminals. At least part of the efferent endings under IHCs in the immature cochlea is represented by medial olivocochlear neurons making direct synaptic contacts with the cell. Pre-hearing OHCs are devoid of direct efferent contacts. In the mature mouse cochlea, afferent synapses typically have a single ellipsoid ribbon per active zone in both inner and outer hair cells. IHCs form afferent synapses only. Lateral olivocochlear neurons synapse onto type I SGNs boutons in close proximity to IHCs, whereas medial olivocochlear neurons contact OHCs directly.

(Scheme drawn by Marcelo J. Moglie.)

Physiology of the MOC Efferents to “Mature” OHC

Two alternative mechanisms for sound amplification have been described in the peripheral auditory system. An old one, shared by non-mammalian and mammalian vertebrates, where amplification results from the nonlinearity in the transduction mechanism itself (Chan & Hudspeth, 2005; Jia & He, 2005; Kennedy et al., 2005) and a more recent one, in which the hair cell receptor potential drives a novel motile process within the lateral membrane of the OHC (Brownell, Bader, Bertrand, & de Ribaupierre, 1985; Dallos, 1992, 2008; Dallos & Evans, 1995). In mammals, OHCs are the principal players underlying cochlear amplification, where hyperpolarization causes the cell to expand along its longitudinal axis and depolarization causes it to contract. This process, known as somatic electromotility, is based on the motor-protein prestin (Zheng et al., 2000), a member of the solute carrier anion-transport family 26 (SLC26) (Elgoyhen & Franchini, 2011; Franchini & Elgoyhen, 2006; Mount & Romero, 2004). Thus, at each place along the cochlear partition, OHCs amplify basilar membrane motion. MOC efferents that contact OHCs are in place to modify the action of the OHCs and, through this, to control the gain of the “cochlear amplifier” (Guinan, 1996; Guinan, 2006). Efferent inhibition can be activated by sound presented to the contralateral ear (Chambers, Hancock, Maison, Liberman, & Polley, 2012; Kujawa, Glattke, Fallon, & Bobbin, 1994; Maison et al., 2012; Muller, Janssen, Heppelmann, & Wagner, 2005). However, most studies of efferent inhibition in animals have been performed by electrical stimulation of efferent axons at the floor of the fourth ventricle and measurement of effects in the cochlea (Guinan, 1996). Thus, MOC stimulation reduces the response at the best frequency measured either at the compound (Galambos, 1956) or single unit response of afferent fibers (Gifford & Guinan, 1987; Wiederhold & Kiang, 1970), IHC receptor potential (Brown & Nuttal, 1984) or basilar membrane motion (Murugasu & Russell, 1996; Russell & Murugasu, 1997). Efferent inhibition also affects cochlear tuning, resulting in a broader tuning curve and a diminished selectivity of afferent neurons (Guinan, 1996; Guinan, 2006). The functional roles of MOC activity are still a matter of intense research, including the control of the dynamic range of hearing (Guinan, 1996), enhance selective attention (Delano, Elgueda, Hamame, & Robles, 2007; Oatman, 1976; Terreros, Jorratt, Aedo, Elgoyhen, & Delano, 2016), the improvement of signal detection in background noise (Dolan & Nuttall, 1988; Kawase, Delgutte, & Liberman, 1993; Winslow & Sachs, 1988), and the protection from acoustic injury (Maison & Liberman, 2000; Maison, Luebke, Liberman, & Zuo, 2002; Patuzzi & Thompson, 1991; Taranda, Maison, et al., 2009).

Synaptic Responses at the MOC-Hair Cell Synapse

Although several neurotransmitters have been described in the efferent system—such as γ-aminobutyric acid (GABA), calcitonin-gene-related peptide, dopamine, and neuropeptides—acetylcholine (ACh) is the main neurotransmitter that mediates fast synaptic transmission between MOC efferents and OHCs (for review see Eybalin, 1993; Sewell, 1996). Schuknecht et al. (1959) provided the first hints of a cholinergic innervation. They reported acetylcholinesterase-labeled processes in the intact cochlea that disappeared after surgical de-efferentation. Further biochemical and immunohistochemical studies supported the hypothesis of a cholinergic innervation in the following years, including choline acetyltransferase immuno-labeled patches in large axosomatic synapses onto OHCs observed by electron microscopy (Eybalin & Pujol, 1987).

The first reports of direct efferent effects onto hair cells came from recordings on fish lateral line, known to have cellular mechanisms similar to those of auditory hair cells (Flock & Russell, 1976; Flock & Russell, 1973). Efferent effects on hair cells were inhibitory, caused hyperpolarizing inhibitory post-synaptic potentials (IPSPs) that were blocked by cholinergic antagonists, and produced a reduction of afferent fiber activity. These results were then extended to auditory hair cells of different vertebrate species, such as frogs (Ashmore & Russell, 1983; Sugai, Yano, Sugitani, & Ooyama, 1992), reptiles (Art, Fettiplace, & Fuchs, 1984; Art, Crawford, Fettiplace, & Fuchs, 1982), birds (Fuchs & Murrow, 1992; Shigemoto & Ohmori, 1991), and guinea pigs (Erostegui, Norris, & Bobbin, 1994; Housley & Ashmore, 1991; Kakehata, Nakagawa, Takasaka, & Akaike, 1993; Nenov, Norris, & Bobbin, 1996; Nenov, Norris, & Bobbin, 1996), indicating that efferent effects are conserved across vertebrate species (Manley & Koppl, 1998). The development of an ex vivo rodent cochlear explant preparation for intracellular recordings from hair cells (Glowatzki & Fuchs, 2000) has accelerated the discovery of the synaptic mechanisms involved in both efferent (Ballestero et al., 2011; Gomez-Casati, Fuchs, Elgoyhen, & Katz, 2005; Goutman, Fuchs, & Glowatzki, 2005; Katz et al., 2004; Lioudyno et al., 2004; Oliver et al., 2000; Wedemeyer et al., 2013) and afferent (Glowatzki & Fuchs, 2002; Goutman, 2012; Goutman & Glowatzki, 2007) synapses of mammalian hair cells. Most experiments in cochlear explants were initially performed in developing IHCs, since they are more tractable for sustained stable recordings. Recently, they have been extended to OHCs and this will be indicated when necessary.

Patch-clamp recordings from hair cells shows that spontaneous or evoked IPSPs and responses to ACh are biphasic and consist of a small inward current followed within milliseconds by a much larger and longer lasting outward K+ current (Figure 3). As described below, the inward current corresponds to the opening of a high-calcium permeable non-selective cationic cholinergic nicotinic receptor (Elgoyhen, Johnson, Boulter, Vetter, & Heinemann, 1994; Elgoyhen et al., 2001; Fuchs & Murrow, 1992; Housley, Batcher, Kraft, & Ryan, 1994) and the outward current which leads to hyperpolarization, to the activation of small-conductance Ca2+-activated SK2 K+ channels (Dulon, Luo, Zhang, & Ryan, 1998; Matthews, Duncan, Zidanic, Michael, & Fuchs, 2005; Nenov et al., 1996; Yuhas & Fuchs, 1999). Unitary inhibitory postsynaptic currents (IPSCs) occur rapidly, with rise and decay time constants of approximately 6 ms and 30 ms, respectively. Since this time course corresponds to the Ca2+ gating of SK channels, it implies a fast coupling between the ionotropic neurotransmitter receptor and the SK channel, which leads to the hyperpolarization of the sensory cell. Moreover, it suggests that rapid, localized changes in subsynaptic Ca2+ levels rather than major changes in intracellular Ca2+ levels are sufficient for correct coupling (Oliver et al., 2000). Nevertheless, other lines of evidence have led to the proposal that release of calcium from an internal store, contributes to activation of the SK channels (Kakehata et al., 1993; Lioudyno et al., 2004; Shigemoto & Ohmori, 1991; Yoshida, Shigemoto, Sugai, & Ohmori, 1994). This includes the existence of an endoplasmic reticulum membrane that is co-extensive to the efferent synaptic contact in OHCs (Fuchs, Lehar, & Hiel, 2014; Gulley & Reese, 1977; Hirokawa, 1978; Saito, 1983), which resembles the sarcoplasmic reticulum of the skeletal muscle and pharmacological evidence suggesting ryanodine-sensitive calcium stores (Evans, Lagostena, Darbon, & Mammano, 2000; Lioudyno et al., 2004). More recent experiments in chicken hair cells have suggested that synaptic cisterns serve primarily as a calcium barrier and sink during low-level synaptic activity (Im, Moskowitz, Lehar, Hiel, & Fuchs, 2014). Whether Ca2+-induced Ca2+-release from internal stores might explain the slow effects reported for the MOC efferents (Sridhar, Brown, & Sewell, 1997; Sridhar, Liberman, Brown, & Sewell, 1995) is still a matter of debate.

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Figure 3. Efferent synaptic responses

Snapshot of a cochlear explant. IHCs are depicted with a dashed black line, and some OHCs in the first row are shown with a dashed white line. Representative spontaneous synaptic current recorded in a P10 OHC from a mouse apical cochlear coil, voltage-clamped at −60 mV (recording performed by Jimena Ballestero). As can be observed, a rapid inward current (mediated by the α9α10 nAChR) is curtailed by a larger and longer-lasting outward current (mediated by the SK2 potassium channel).

(Adapted from Elgoyhen & Katz, 2012.)

Most recordings from OHCs have been performed in apical regions of the cochlea, since they are less challenging than those from the basal region. Recent findings have shown that large conductance, Ca2+- and voltage-gated (BK) potassium channels also contribute to efferent inhibition in basal, high-frequency rodent OHCs after the onset of hearing (Wersinger, McLean, Fuchs, & Pyott, 2010). BK channels underlie faster synaptic IPSCs waveforms than SK channels. Thus, IPSCs recorded from basal high-frequency OHCs expressing BK channels are briefer than IPSCs recorded from apical low-frequency OHCs that do not express BK channels (Rohmann, Wersinger, Braude, Pyott, & Fuchs, 2015). Moreover, immature high-frequency OHCs before the developmental onset of BK channel expression also have longer IPSCs, as do OHCs of BKα(-/-) mice lacking the pore-forming α-subunit of BK channels compared to BKα(+/+) littermates (Rohmann et al., 2015). In vivo efferent-mediated inhibition of distortion product otoacoustic emissions has been analyzed in BK knockout mice, indicating that both BK and SK channels contribute to the effect (Maison, Pyott, Meredith, & Liberman, 2013). In addition, immunostaining has shown BK- and SK2-positive puncta at the basal pole of OHCs, colabeling with anti-synaptophysin, suggesting that each of these puncta is located directly opposite to an efferent terminal. A gradient of expression is observed along the cochlea, since BK expression in the OHC area is stronger in the basal half, whereas SK2 expression is stronger in the apical half. The consequence of this BK/SK2 gradient to efferent function is still unknown (but see below).

The Cholinergic Nicotinic Hair Cell Receptor

Although the existence of an cochlear efferent cholinergic innervation was known since the 1960s, an experimental conundrum existed derived from the baroque pharmacological profile of the receptor, which is not activated neither by nicotine nor muscarine and blocked by atropine, nicotine, strychnine, α-bungarotoxin, d-tubocurarine, and bicuculline (Blanchet, Erostegui, Sugasawa, & Dulon, 1996; Doi & Ohmori, 1993; Fuchs & Murrow, 1992; Housley & Ashmore, 1991; Kakehata et al., 1993; Shigemori & Ohmori, 1990, 1991; Yoshida et al., 1994). This profile remained at odds with the classical pharmacological classification of cholinergic receptors into either metabotropic muscarinic or ionotropic nicotinic. Indeed, the receptor was in fact proposed to be a muscarinic one, coupled to a guanine nucleotide binding protein (G-protein) which triggers metabolic cascades of InsP3 and Ca2+ (Kakehata et al., 1993; Shigemoto & Ohmori, 1990, 1991; Yoshida et al., 1994). It was not until the cloning of the α9 cholinergic nicotinic receptor subunit that the molecular nature of the receptor present at the MOC-hair cell synapse, both in developing IHCs and adult OHCs was deciphered (Elgoyhen et al., 1994). The additional cloning of the α10 subunit (Elgoyhen et al., 2001; Lustig, Peng, Hiel, Yamamoto, & Fuchs, 2001; Sgard et al., 2002) completed the subunit composition of the cholinergic nicotinic receptor present at the MOC-hair cell synapse. Mutant mice lacking either the α9 (Vetter et al., 1999) or the α10 (Vetter et al., 2007) and a α9 knockin mouse model bearing a point mutation in the pore region of the channel (Taranda, Maison, et al., 2009), have unequivocally demonstrated that both nAChR subunits are needed for ACh-mediated MOC efferent effects. By comparison of the properties of recombinant α9α10 nAChRs expressed in Xenopus oocytes (Ballestero et al., 2005; Elgoyhen et al., 1994; Elgoyhen et al., 2001; Ellison et al., 2006; Johnson, Martinez, Elgoyhen, Heinemann, & McIntosh, 1995; McIntosh et al., 2005; Rothlin, Verbitsky, Katz, & Elgoyhen, 1999; Rothlin et al., 2003; Verbitsky, Rothlin, Katz, & Elgoyhen, 2000) with those of native receptors present in hair cells (Ballestero et al., 2011; Elgoyhen et al., 2001; Gomez-Casati et al., 2005), it is now well established that the receptor is a pentameric assembly α9 and α10 subunits (Elgoyhen & Katz, 2012) with a likely α92α103 stoichiometry (Plazas, Katz, Gomez-Casati, Bouzat, & Elgoyhen, 2005). Thus, it belongs to the family of pentameric ligand-gated ion channels which in mammals comprises nicotinic acetylcholine receptors (nAChRs), serotonin type 3 (5-HT3) receptors, γ-aminobutyric acid type A (GABAA) receptors, glycine receptors, and zinc-activated ion channels (Nemecz, Prevost, Menny, & Corringer, 2016). In this regard, it is worth noting that it retains pharmacological properties of other members of the family, since it is blocked with high potency by the glycinergic antagonist strychnine, the 5-HT3 receptor antagonists ICS 205-930, ondansetron and granisetron and the GABAA receptor antagonist bicuculline (Elgoyhen et al., 2001; Rothlin et al., 2003).

An additional peculiarity of the α9α10 nAChR is its evolutionary history. It was originally proposed to be the most primitive of all nAChR subunits, with the closest similarity with the hypothetical ancestor that gave rise to the family (Elgoyhen & Katz, 2012; Fritzsch & Elliott, 2017; Rothlin et al., 1999), based on its pharmacological properties and on the fact that α9 can form functional homomeric receptors. However, this might not be the case since the last common ancestor of chordates and invertebrates had an α7 subunit (possibly several), an α9 subunit and the muscle/neuronal-type subunits (Dent, 2006). Although both α9 and α10 subunits belong to the nAChR family, they are distant members based upon amino acid sequence homology (Elgoyhen et al., 1994; Elgoyhen et al., 2001). Moreover, a phylogenetic and molecular evolutionary analysis has shown that the gene encoding the α10 subunit (CHRNA10) has been under positive selection pressure only in the mammalian lineage (Elgoyhen & Franchini, 2011; Franchini & Elgoyhen, 2006). This suggests that CHRNA9 and CHRNA10 genes appeared after a gene duplication event from a common ancestor and co-existed without much functional diversion, until at some point during the course of evolution of the mammalian lineage changes started to accumulate in CHRNA10. Since during evolution, purifying (or negative) selection, i.e., the removal of functionally deleterious mutations, prevails in most protein-coding DNA sequences, the acquisition of amino acid changes in the coding region of the α10 nAChR subunit might indicate that mammalian α9α10 nAChR increased its fitness by acquiring novel functional properties which might have evolved with the specialization of mammalian hearing (Elgoyhen & Franchini, 2011). It is worth noting that prestin, the protein responsible for somatic electromotility and active mechanism for amplification in mammalian OHCs as well as the giant spectrin βV, a major component of the OHC´s cortical cytoskeleton, have also been under positive selection pressure only in mammals (Cortese et al., 2017; Franchini & Elgoyhen, 2006). Cholinergic efferent feedback is found in all vertebrate species (Manley & Koppl, 1998; Simmons, 2002) and α9 and α10 nAChRs have been found expressed in auditory and vestibular hair cells of all vertebrate species analyzed (Elgoyhen et al., 1994; Elgoyhen et al., 2001; Glowatzki et al., 1995; Hiel, Elgoyhen, Drescher, & Morley, 1996; Lustig, Hiel, & Fuchs, 1999; Morley, Li, Hiel, Drescher, & Elgoyhen, 1998; Morley & Simmons, 2002; Simmons & Morley, 1998). Thus, one could speculate that the evolution of CHRNA10 has endowed the mammalian auditory system feedback an α9α10 nAChR fit to control prestin-driven somatic electromotility, a capacity that is not required in non-mammalian species. One clear feature that differs between mammalian and non-mammalian α9α10 is their Ca2+ permeability (Lipovsek et al., 2014; Lipovsek et al., 2012).Whereas rat receptors have a high (pCa2+/pMonovalents ∼10) Ca2+, chicken α9α10 receptors have a much lower permeability (∼2) to this cation, comparable to that of neuronal α4β2 receptors. It has been speculated that the selection pressure might have derived from the fact that large conductance, calcium and voltage-gated (BK) potassium channels are expressed at efferent contacts and responsible for ACh-mediated hyperpolarization of OHCs in high frequency regions of the rat cochlea (Wersinger et al., 2010). Calcium affinity of BK channels is 2 orders of magnitude lower than that of SK channels (Fakler & Adelman, 2008), thus requiring higher calcium influx for activation compared to SK channels present in cochlear low-frequency regions or the chicken basilar papilla. Taken together these functional adaptations in cochlear proteins might have occurred to accommodate the higher frequency hearing capacities of mammals (Manley, 2017).

All nicotinic receptors serve fast excitatory synaptic transmission in the nervous system (Karlin, 2002). In contrast, neuronal fast inhibition is brought about by the activation of either GABAA or glycine receptors which are ligand-gated Cl- channels (Burgos, Yevenes, & Aguayo, 2016; Moss & Smart, 2001). Given the presence of efferent GABAergic innervation to hair cells, the existence of a fast inhibitory neurotransmission brought about by the activation of a nicotinic cholinergic Ca2+- permeable α9α10 receptor coupled to SK and/or BK channels, is a self-standing feature. One could argue that K+-versus Cl--driven hyperpolarization needed to modulate electromotility is more pronounced at the -60 mV resting potential of OHCs (O'Beirne & Patuzzi, 2007). In addition, fast K+ instead of Cl- -mediated hyperpolarization might be required to avoid a direct perturbation of prestin extrinsic voltage sensors which are brought about by the intracellular anions chloride and bicarbonate (Oliver et al., 2001). However, α9α10 nAChR-mediated activation of SK channels is also present in non-mammalian and vestibular hair cells, which lack-prestin-driven electromotility. Thus, the evolutionary pressures leading to the appearance of a Cl- independent fast synaptic inhibition mechanism are still an enigma.

Molecular Actors at the MOC-Hair Cell Synapse

Neurotransmitter release at central and peripheral synapses is triggered by presynaptic Ca2+ entry (Katz & Miledi, 1969) through multiple voltage-gated Ca2+ channels (VGCC) including N-type, P/Q- type and R-type (Catterall, 2000; Catterall & Few, 2008). Electrophysiological and pharmacological experiments have shown that at P9-11 release at efferent-IHC synapses derives from the activation of both N (Cav2.2) and P/Q-type (Cav2.1) VGCC closely associated with the release machinery (Zorrilla de San Martin, Pyott, Ballestero, & Katz, 2010) (Figure 4). In addition, Ca2+ influx via L-type VGCCs together with membrane depolarization activates efferent terminal BK channels (Zorrilla de San Martin et al., 2010). As reported in other neurons this would accelerate the repolarization of the terminal membrane (Berkefeld & Fakler, 2008; Berkefeld, Fakler, & Schulte, 2010; Berkefeld et al., 2006) and tight regulate transmitter release by exerting a negative feedback (Raffaelli, Saviane, Mohajerani, Pedarzani, & Cherubini, 2004; Robitaille, Garcia, Kaczorowski, & Charlton, 1993). The Ca2+ channels involved in transmitter release at MOC-OHCs are still to be determined. Electron microscopy experiments with immunogold labeling have shown OHC pre and post-synaptic expression of BK channels (Sakai, Harvey, & Sokolowski, 2011), suggesting the presence of a similar negative feedback of transmitter release.

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Figure 4. Representation of the molecules at the efferent synapse

Schematic representation of the molecules and mechanisms involved in synaptic transmission at MOC-hair cell synapses (right side). ACh release is supported by both P/Q and N-type VGCC. BK channels activated by Ca2+ entering through L-type VGCC accelerate action potential repolarization and thus diminish the amount of ACh being released. GABA probably co-released with ACh, activates presynaptic GABAB(1a,2) receptors, which inhibit ACh release by altering the activity of P/Q-type VGCC. The inhibitory postsynaptic response is mediated by α9α10 nAChR coupled to the activation of SK2 potassium channels. Ca2+-induced Ca2+ release from the postsynaptic cisterns closely apposed to the IHC synaptic region probably also contributes to SK2 activation. Nitric oxide synthetized by the IHC enhances transmitter release by the MOC synaptic terminals acting as a retrograde messenger. Glutamate released from the efferent synapses (left side) activates group I mGluRs on presynaptic efferent terminals and enhances ACh release and efferent synaptic inhibition to the IHC.

(SERCA: sarcoendoplasmic reticulum calcium ATPase; RyR: ryanodine receptor; NOS: nitric oxide synthase; NO: nitric oxide).

In addition to Ca2+-triggered exocytosis, neuronal transmitter release is regulated by the activation of presynaptic receptors present in the synaptic terminal. Depending on the ligand that activates the presynaptic receptor, they are distinguished into auto- and heteroreceptors, the former controlling the release of their endogenous agonist, the latter controlling the release of transmitters other than their endogenous ligand. The presence of cholinergic presynaptic autoreceptors on MOC efferent terminals has not been investigated. However, presynaptic GABAB (Wedemeyer et al., 2013) and group I metabotropic glutamate mGluR1 (Ye, Goutman, Pyott, & Glowatzki, 2017) heteroreceptors are present at these cholinergic terminals and provide negative and positive feedback for transmitter release, respectively (Figure 4).

During the developmental critical period immature IHCs fire action potentials and release glutamate into the synaptic cleft. This activates ionotropic glutamate receptors on afferent dendrites of the spiral ganglion neurons (Grant, Yi, & Glowatzki, 2010). Each IHC action potential can release hundreds of glutamate-filled vesicles (Glowatzki & Fuchs, 2002) and therefore, glutamate spillover is likely to occur under physiological conditions (Ye et al., 2017). In fact, activation of group I metabotropic glutamate receptors (mGluR1s) enhances ACh release, most likely through the activation of presynaptic mGluR1s present in efferent terminals (Ye et al., 2017). It has been reported that in the central nervous system mGluRs reduce currents through L-type Ca2+ channels (Pin & Duvoisin, 1995; Sahara & Westbrook, 1993). Thus, group I mGluRs activation in the developing cochlea might provide a positive feedback to enhance efferent inhibition by suppressing L-type Ca2+ channels known to be present in efferent terminals (Zorrilla de San Martin et al., 2010), prevent the activation of BK channels, and prolong terminal depolarization and neurotransmitter release (Ye et al., 2017). Whether the same mechanism operates in MOC-OHC synapses has not been evaluated.

Antibodies against either GABA or its synthesizing enzyme, glutamate decarboxylase (GAD), have shown immunoreactivity in cell bodies of the superior olivary complex and in efferent terminals located below IHCs and OHCs. Moreover, cochlear efferent terminals demonstrate GABA uptake, suggesting GABA as a second neurotransmitter of the efferent system (for review see (Eybalin, 1993)). Studies in mice have provided evidence that virtually all olivocochlear endings in OHCs, including cholinergic and GABAergic projections, arise from the MOC system; whereas those in the IHC area arise almost exclusively from the LOC system (Maison et al., 2003). The longitudinal distribution of GABAergic terminals beneath OHCs varies from species to species: apical half in guinea pigs and throughout the cochlea in mouse. Immunoelectron microscopy studies have provided strong evidence for ChAT and GAD colocalization in efferent terminals on OHCs throughout the rat cochlea (Dannhof, Roth, & Bruns, 1991). A study in mice has further suggested the complete congruence of GABAergic and cholinergic markers in the IHC and OHC areas (Maison et al., 2003), suggesting that ACh and GABA are released from the same terminal. In this regard, since the advent of optogenetics, corelease of fast neurotransmitter is emerging as a common theme of central neuromodulatory systems (Granger, Mulder, Saunders, & Sabatini, 2016; Hnasko & Edwards, 2012). For example, corelease of ACh and GABA from cholinergic forebrain neurons has been recently reported (Saunders, Granger, & Sabatini, 2015).The function of the GABAergic innervation to hair cells and the exact molecular targets are poorly understood. Mouse lines with targeted deletions of GABAA receptor subunits have suggested that the GABAergic component of the OC system is needed for the long-term maintenance of hair cells and neurons in the inner ear (Maison, Rosahl, Homanics, & Liberman, 2006). Furthermore, the analysis of GABAB1 knock-out mice has indicated that GABAergic signaling is required for normal OHC amplifier function at low sound levels and OHC responses to high-level sound, since they show increased resistance to permanent acoustic injury (Maison, Casanova, Holstein, Bettler, & Liberman, 2009). GABA-mediated changes in the stiffness and motility of OHCs have been also reported (Batta, Panyi, Szucs, & Sziklai, 2004; Zenner, Gitter, Rudert, & Ernst, 1992). Although one early study reported that guinea pig OHCs hyperpolarize in the presence of GABA (Gitter & Zenner, 1992), recent studies in mouse P9-11 IHCs and P12-14 OHCs show no evidence of currents when GABA is applied, suggesting the lack of postsynaptic GABAA receptors (Wedemeyer et al., 2013). Lack of GABAA-mediated fast postsynaptic responses is further demonstrated by the fact that no postsynaptic currents in response to either high K+ or electrical stimulation of MOC efferent axons are seen in OHCs (Ballestero et al., 2011; Oliver et al., 2000) and IHCs (Glowatzki & Fuchs, 2000; Gomez-Casati et al., 2005) when the α9α10 nAChR is pharmacologically blocked or in α9 knockout mice (Vetter et al., 2007). Moreover, GABAB receptors are not expressed either in postnatal (Wedemeyer et al., 2013) or adult hair cells (Maison et al., 2009), further indicating a lack of postsynaptic GABAB-mediated action. Therefore, a presynaptic site of action for GABA is expected. This is indeed the case, since GABA downregulates the amount of ACh released both at developing efferent IHC and OHCs. At least in IHCs this is mediated by presynaptic GABAB(1a,2) receptors coupled to the inhibition of P/Q-type VGCCs (Wedemeyer et al., 2013).

In summary, tight control of ACh release from efferent terminals is exerted through the presence of presynaptic neurotransmitter receptors, namely GABAB (Wedemeyer et al., 2013) and group I metabotropic glutamate receptor mGluR1 (Ye et al., 2017). In brief, whereas GABA inhibits, glutamate enhances ACh release, providing a negative and positive feedback to efferent inhibition, respectively. GABA most likely has a neuronal efferent origin, whereas glutamate is a spillover from the nearby IHC endogenous release of glutamate. This tight regulation of ACh release at MOC terminals might act in concert with the short-term synaptic plasticity phenomena known to shape the strength of cochlear inhibition.

Short-Term Synaptic Plasticity

A common property of most synapses is that they can keep track of their previous activity by means of synaptic plasticity. Each synapse can integrate several forms of plasticity leading to changes in synaptic strength and this plays a critical role in information transfer and neural processing. Thus, synaptic strength can be reduced for hundreds of milliseconds to seconds leading to depression, or it can be enhanced during hundreds of milliseconds to seconds resulting in facilitation. In addition, enhancement can last tens of seconds, a phenomenon known as post-tetanic potentiation (Fioravante & Regehr, 2011; Zucker & Regehr, 2002).

MOC efferents respond to sound with sensitivity and tuning like that of type I cochlear afferents (Liberman & Brown, 1986; Robertson & Gummer, 1985) and provide a feedback loop for cochlear gain control. The correct operation of this feedback requires a careful match between the acoustic stimulus and the strength of cochlear inhibition. This is mainly brought about by efferent synaptic plasticity both at the developing efferent-IHC and MOC-OHC synapses. A low probability of release at rest, and facilitation of responses at high frequency stimulation, is a common feature of efferent synapses (Art et al., 1984; Ballestero et al., 2011; Goutman et al., 2005).

The first reports of short-term synaptic plasticity in efferent terminals were described in turtle hair cells, where the resting probability of release at the hair cell efferent synapse was low, ranging from 0.08 to 0.3, but facilitated markedly during repetitive stimulation of the efferent axons (Art et al., 1984). Thus, single shocks to the efferents generated hair cell membrane hyperpolarization with an average amplitude of less than 1 mV. The size of the post-synaptic potential grew markedly to a maximum of 20–30 mV when trains of shocks were applied. Similar results have been found in rat P7–11 IHCs. Single shocks at frequencies less than 2 Hz evoked small IPSCs with a mean probability of 0.35. With repeated stimulation, IPSCs are both larger and more prolonged, likely due to facilitation and summation. For trains of 10 shocks IPSCs reliably reached more than 100 pA in amplitude (Goutman et al., 2005). Nitric oxide retrograde signaling from the hair cell to the efferent terminal has been proposed to contribute to this facilitation (Kong, Zachary, Rohmann, & Fuchs, 2013).

Similar mechanisms have been reported for the MOC-OHC synapse with a low resting probability of release. Facilitation combined with postsynaptic summation significantly increase the reliability and strength of synaptic transmission during repetitive efferent activity (Ballestero et al., 2011). The poor efficacy of synaptic transmission at the MOC–OHC at low frequency of stimulation is reflected by the low quantum content of transmitter release (m = 0.3). The overlap between spontaneous and evoked IPSCs amplitude histograms has led to the proposal that, on average, one vesicle is released upon arrival of an action potential to the MOC–OHC efferent terminal. The observation that in mice, OHCs from the apical region (where recordings were performed) are usually innervated by one efferent fiber (Maison et al., 2003) and that one efferent axon only rarely makes more than one contact with each OHC (Warr & Boche, 2003; Wilson, Henson, & Henson, 1991) is consistent with the idea that only one bouton will be activated each time an electrical shock is applied (Ballestero et al., 2011). However, shortage of synaptic vesicles cannot account for the low resting probability of release since efferent terminals have large numbers of vesicles (Fuchs et al., 2014; Lenoir, Schnerson, & Pujol, 1980). The implication of this result is that the efferent terminal is prepared to recruit synaptic vesicles when stimulation is repetitive and at sufficiently high frequencies so that facilitation of transmitter release can occur. The unreliability of transmitter release at the MOC–OHC synapse at low frequency stimulation has been attributed to the stochastic nature of release, rather than to axonal threshold variations or conduction failures (Ballestero et al., 2011). The negative feedback loop provided by the coupling between L-type voltage-gated calcium channels and BK channels (Zorrilla de San Martin et al., 2010) may operate to decrease synaptic output. Thus, as reported by Ballestero et al (2011) synaptic events occur sparsely at 10 Hz but increase in frequency and amplitude of individual responses as stimulation frequency increases (Figure 5). As expected, a sustained and enhanced hyperpolarization of the OHCs is observed in response to high-frequency MOC stimulation (Figure 6). The strengthening of synaptic transmission at high frequency stimulation of MOC terminals is accounted for by both facilitation and summation of OHCs synaptic responses. Ballestero et al. (2011) have evaluated the relative contribution of summation and facilitation by simulating the postsynaptic responses at different stimulation frequencies and concluded that the combined effect of both phenomena are needed to produce a simulated response most closely resembling the experimental data (Figure 7). Since the increase in the postsynaptic response during repetitive stimulation correlates with an increase in the probability of release and not with an increase in the mean amplitude of IPSCs, facilitation is due to a presynaptic mechanism. In addition, the relatively slow decay of combined nAChR and SK2 eIPSCs result in temporal summation.

Efferent Innervation to the CochleaClick to view larger

Figure 5. Facilitation of efferent transmitter release

Facilitation of transmitter release contributes to the increase in the postsynaptic response during high-frequency stimulation. Responses to 10 shock trains (gray traces) were applied at different frequencies (A–E). The black trace is the average response of 100 repetitions at each frequency.

(Reproduced from Ballestero et al., 2011.)

Efferent Innervation to the CochleaClick to view larger

Figure 6. Hyperpolarization in response to efferent stimulation

IPSPs obtained in OHCs in response to 25 and 50 Hz stimulation trains in the current-clamp mode (gray traces). The black trace is the average response obtained upon 100 repetitions of the train.

(Reproduced from Ballestero et al., 2011.)

Efferent Innervation to the CochleaClick to view larger

Figure 7. Summation of efferent responses

Summation contributes to the increment of the postsynaptic response during high-frequency stimulation. Simulated responses were derived from a response (A, inset) considering only temporal summation (gray traces) or facilitation by taking into account the change in the probability of release (black traces) for every shock. Simulation plots of normalized current versus pulse number were constructed considering only summation (B) or summation and facilitation (C). D: Experimental plot of normalized current versus pulse number. Summation and facilitation best fit the experimental data. E–H: Representative traces of the simulated single sweep responses.

(Reproduced from Ballestero et al., 2011.)

Synapses with low initial probability of release and strong facilitation have been postulated to work as high-pass filters, since they fail to transmit during low frequency action potentials but facilitate during sustained firing in a frequency-dependent manner (Atluri & Regehr, 1996; Jackman & Regehr, 2017). This would allow the MOC efferent feedback to operate in a kind of failsafe mode. Thus, OHCs would ignore spontaneous or inadvertent activity and only respond when efferents are strongly stimulated. Short-term plasticity of the MOC–OHC synapse allows this scaling of inhibition to MOC activity encoding graded levels of efferent feedback. This is important to provide a fine tuning of cochlear amplification, since efferent firing frequency increases linearly with sound intensity (Brown, Kujawa, & Liberman, 1998; Liberman & Brown, 1986; Robertson & Gummer, 1985). In vivo studies of the MOC effect on auditory function highly resemble the properties of the MOC–OHC synapse: brainstem electrical stimulation of MOC neurons relies on high-frequency trains rather than single shocks to inhibit auditory function (Galambos, 1956; Gifford & Guinan, 1987; Mountain, 1980; Wiederhold & Kiang, 1970) and the strength of the efferent effect increases as the frequency of stimulation increases, (Art et al., 1984; Brown & Nuttal, 1984; Flock & Russell, 1973; Galambos, 1956; Gifford & Guinan, 1987; Wiederhold & Kiang, 1970). (See Figure 8.) The increase of MOC firing rate with sound intensity is consistent with the proposal that the efferent system protects the inner ear from noise-induced trauma (Kujawa & Liberman, 1997; Patuzzi & Thompson, 1991; Rajan, 1988; Rajan, 2000; Taranda, Maison, et al., 2009).

Efferent Innervation to the CochleaClick to view larger

Figure 8. In vivo studies of the MOC effect on auditory function highly resemble the properties of the MOC–OHC synapse

MOC neurons rely on high-frequency trains rather than single shocks to inhibit auditory function, and the strength of the efferent effect increases as the frequency of stimulation increases. A: Relationship between the frequency of MOC activation and inhibition of afferent activity in the cat (Galambos, 1956; and Gifford & Guinan, 1987) and in the turtle [Art & Fettiplace (1984)]. Left-axis: Efferent effect quantified as the ratio between the amplitude of the N1 component of the compound action potential. Right-axis: Increase in sound intensity (threshold shift in decibels) necessary to evoke an afferent discharge as a function of the efferent stimulation frequency. B: Increment in eIPSC amplitudes in response to efferent stimulation at different frequencies.

(Reproduced from Ballestero et al., 2011.)

MOC Efferent Synaptogenesis

Nearly all vertebrate hair-cell sense organs have an efferent innervation. Efferent innervation of hair cells is as old as hair cells themselves and co-evolved with the vertebrate inner ear (Manley, 2000, 2017; Manley & Koppl, 1998). The most ancient efferents synapsed on a range of vestibular end organs and lateral line providing a gross control of hair cells. It has been suggested that efferents evolutionarily derived from facial branchial motor neurons, based upon their spatial and developmental associations, as well as their cholinergic nature (Fritzsch & Elliott, 2017; Roberts & Meredith, 1992). This hypothesis is further based on the fact that after ear ablation developing efferents join the facial motor neurons, most likely reverting to their ancestral condition (Fritzsch, 1999). Moreover, inner ear efferent neurons and motor neurons share a common embryological origin (Fritzsch, 1999). For an extended review of the development of the efferent system see (Simmons, 2002).

Efferent axons innervate the mouse cochlea as early as embryonic day 13 (Bruce et al., 1997; Fritzsch, 1999). The molecular cues that guide efferent axons to the inner ear are not well understood. Moreover, inner ear afferent fibers may serve as a substrate to direct efferent fibers to their sensory targets (Fritzsch, Pirvola, & Ylikoski, 1999). During cochlear development, there are numerous efferent axosomatic synapses on IHCs that disappear in the adult cochlea (Simmons, Bertolotto, Kim, Raji-Kubba, & Mansdorf, 1998; Simmons, Mansdorf, & Kim, 1996; Simmons, Manson-Gieseke, Hendrix, & McCarter, 1990; Simmons, Moulding, & Zee, 1996). Reconstructions of the efferent innervation in hamsters has shown that anterograde biocytin and horseradish peroxidase labeled efferent axons terminate on or below IHCs prior to P5. After P5, labeled axons terminate on both IHCs and OHCs and after P10, the majority of labeled axons terminate on the OHCs. At the electron microscopy level, small labeled terminals containing densely packed synaptic vesicles are observed both adjacent to IHCs (axosomatic) as well as apposed to afferent and efferent fibers below IHCs prior to P5. By P10, large labeled terminals are found only in direct contact with OHCs and no longer on IHCs (Simmons et al., 1990). Similar results have been obtained in rats and cats (Bruce et al., 2000; Perkins & Morest, 1975). The developmental changes in axosomatic synaptic contacts in IHCs are matched by changes in ultrastructural features such as the synaptic cisterns, which are present at early postnatal ages and disappear from IHCs after the onset of hearing (Ginzberg & Morest, 1984). These transient axosomatic efferent contacts to IHCs are of MOC origin (Simmons et al., 1990) and suggest that MOC axons first innervate IHCs prior to the onset of hearing (second postnatal week in altricial rodents) before terminating on OHCs. This is reminiscent of a waiting period below an intermediate target, similar to that described in the development of thalamocortical projections (Ghosg & Shatz, 1993). The mechanisms involved in this period of MOC synaptic transition from inner to OHCs are not known. Competition of afferent and efferent terminals for synaptic space below OHCs might explain the coincidence of efferent arrival and the decrease of afferent terminals on OHC (Pujol, 1985).

The transient direct efferent innervation of IHCs is mirrored by developmental regulation of expression of the CHRNA9 and CHRNA10 genes, suggesting the presence of cholinergic synapses. In situ hybridization studies have shown that α9 nAChR subunit mRNA is expressed as early as E18, reaching its maximum near birth in IHCs and P10 in OHCs. A transgenic mouse with a GFP reporter in the CHRNA9 locus resolves a similar expression pattern (Zuo, Treadaway, Buckner, & Fritzsch, 1999). Moreover, CHRNA9 expression is still observed in adult IHCs even after retraction of axosomatic MOC contacts (Elgoyhen et al., 1994; Luo, Bennett, Jung, & Ryan, 1998; Simmons & Morley, 1998; Zuo et al., 1999). On the other hand, α10 nAChR subunit mRNA expression is observed as from E21, peaks around P1 in IHCs and P10 in OHCs (Morley & Simmons, 2002). Contrary to that described for α9, α10 expression is not present in adult IHCs and disappears by P21 (Elgoyhen et al., 2001; Morley & Simmons, 2002). Homomeric α9 receptors expressed in Xenopus oocytes are functional, albeit rendering current amplitudes which are ~ 100 times smaller than those of α9α10 heteromeric receptors (Elgoyhen et al., 1994; Elgoyhen et al., 2001). However, although small ACh-gated currents are observed in OHCs of α10 knock-out mice, IHCs lack ACh responses before the onset of hearing in these mice (Vetter et al., 2007). Moreover, IHCs of wild-type mice lack responses after the onset of hearing (Katz et al., 2004). Therefore, the expression of α9 in the absence of α10 subunits in IHCs with no direct efferent contacts after the onset of hearing is intriguing. One could speculate, although it is not tested, that the high permeable α9 nAChR has an alternative, not purely “ionotropic,” function in mature IHCs to modulate the release of glutamate through ribbon synapses.

Acetylcholine responses and synaptic currents in developing IHCs were first reported in an acute ex vivo rat cochlear explant by Glowatzki & Fuchs (2000). Acetylcholine responses, but no synaptic currents, are detected by P0 in rat apical cochlear IHCs and are mediated by α9α10 nAChRs, since they are blocked by strychnine, curare, and RgIA but are not coupled to SK channels (Roux, Wersinger, McIntosh, Fuchs, & Glowatzki, 2011). From P1 onward, punctate α-Btx labeling and the first clusters of SK2-immunoreactivity are detected in a fraction of IHCs, thus indicating histological signs of synapse formation. This is accompanied by SK-coupled ACh responses and the first evidence of synaptic currents. Moreover, IHC with efferent synaptic activity are only seen when the SK current is present, suggesting that SK2 expression is correlated with functional synapses (Roux et al., 2011). This might indicate that the expression of SK2 channels is causally related to the onset of efferent synaptic function and required for the assembly, trafficking, and/or anchorage of the nAChR macromolecular synaptic complex. Although not tested, proteins known to form a macromolecular complex with SK2 channels, such as calmodulin, protein kinase CK2, and protein phosphatase 2A (Bildl et al., 2004), might also be developmentally regulated and be the linking molecules of the SK2 channel with the nAChR macromolecular complex. Given the sign reversal when nAChRs are coupled to SK channels, one could speculate that SK-mediated hyperpolarization compared to ACh-mediated depolarization might be essential for synaptic maturation. In addition, SK channels are also important for the maintenance of the synapse, since synaptic currents disappear with the loss of functional SK currents after the onset of hearing (Katz et al., 2004). A fundamental role for SK2 channel in synapse formation and stability is supported by the lack of ACh response and efferent synaptic activity in P6–P12 IHCs of SK2 knockout mice, despite normal levels of α9 and α10 nAChR mRNAs (Kong, Adelman, & Fuchs, 2008). In addition, efferent innervation progressively degenerates in SK2 (Kong et al., 2008; Murthy, Maison, et al., 2009), but not in either α9 (Murthy, Taranda, Elgoyhen, & Vetter, 2009; Vetter et al., 1999) or α10 (Vetter et al., 2007) deficient mice. Moreover, the finding that in a transgenic mouse with constitutive expression of the α10 subunit, IHCs still lack ACh responses after the onset of hearing (Taranda, Ballestero, et al., 2009), indicates that the expression of the CHRNA9 and CHRNA10 genes does not suffice for the assembly of functional α9α10 nAChRs and probably requires chaperon proteins which are not expressed as from ~ P12.

Experiments in isolated OHCs from gerbils and rats suggest that the onset of acetylcholine-induced responses begins on or after P6. At this stage currents are inward and reverse near 0 mV suggesting that the nAChR is not coupled to the SK channel (Dulon & Lenoir, 1996; He & Dallos, 1999). This response becomes functionally mature by P12 when coupling to the SK potassium current is always observed. The development of acetylcholine-induced responses in isolated OHCs coincides with the time period when OHCs develop motility before the onset of auditory function (He & Dallos, 1999). Moreover, it mirrors prestin OHCs lateral membrane labeling which is very low at P0, has a prominent increase between P6 and P9 and reaches adult levels at P9 in the basal turn of the cochlea, at P10–P11 in the middle turn, and at P12 in the apical turn (Belyantseva, Adler, Curi, Frolenkov, & Kachar, 2000).

The Critical Period

The precise organization and physiological properties of neuronal circuits and topographic maps in the mature brain are often established by developmental processes that involve reorganization and fine tuning of immature synaptic networks (Goodman & Shatz, 1993). Therefore, establishing correctly organized and appropriately adjusted synaptic circuits is a crucial event during "critical periods" of brain development, an early postnatal epoch of plasticity during which large-scale changes take place. One key issue discussed in developmental neuroscience is the question of how the specificity of synaptic connections in these networks are established in such a precise manner. Several major factors are thought to play a crucial role. In general, internal factors (i.e., genetically determined) must be distinguished from external factors (i.e., environmental). On the other hand, activity-dependent developmental processes play a key role and are subdivided into those associated with spontaneous activity and those depending on sensory-evoked activity.

The auditory system in many mammals is very immature at birth but precisely organized in adults. Hearing onset, defined as the ability of neurons to reliably respond to normal intensities of airborne sound, occurs after the second postnatal week in altricial rodents (Blatchley, Cooper, & Coleman, 1987; Puel & Uziel, 1987). Consequently, the early steps in the generation of the basic auditory brainstem circuitry are not influenced by acoustically driven activity. However, it is not established in an activity-independent manner, because spontaneous activity, giving rise to glutamate release from IHCs and to the subsequent activation of auditory nerve fibers that discharge bursts of Ca2+ action potentials, comes into play to guide this process (Glowatzki & Fuchs, 2000; Johnson, Kuhn, et al., 2013; Jones, Jones, & Paggett, 2001; Lippe, 1994). With maturation, a number of changes reduce IHC spiking. These include a reduction in the number of voltage-gated calcium channels, and the onset of a large, voltage-gated potassium conductance (Marcotti, Johnson, Holley, & Kros, 2003). These changes trigger the transformation of a developing epithelium with active synaptogenesis to a sensing epithelium, where synaptic contacts have stabilized and mechanical input is transduced into receptor potentials in IHCs in a graded manner.

The spontaneous activity in auditory nerve fibers before the onset of hearing is propagated to central auditory nuclei (Tritsch et al., 2010) and is essential for the survival of target neurons in the cochlear nucleus, accurate wiring of auditory pathways, and the refinement of tonotopic maps in auditory nuclei (Friauf & Lohmann, 1999; Kandler, 2004; Leake, Hradek, Chair, & Snyder, 2006). Synchronous activity among groups of hair cells along the length of the cochlea could help establish and maintain tonotopic segregation of neuronal projections in auditory pathways through hebbian like plasticity (Kandler, 2004; Kotak & Sanes, 1995) and help further refine and maintain synaptic connections (Erazo-Fischer, Striessnig, & Taschenberger, 2007; Leake et al., 2006). Thus, changes in afferent activity are known to lead to changes in synaptic properties in higher brainstem nuclei (Erazo-Fischer et al., 2007; Lippe, 1994; Sonntag, Englitz, Kopp-Scheinpflug, & Rubsamen, 2009). This could derive from changes in the pattern of action potential activity in IHCs which alter the developmental changes that occur in the Ca2+ dependence of neurotransmitter release at the cell’s ribbon synapses before the onset of hearing (Johnson, Kuhn, et al., 2013; Johnson, Wedemeyer, et al., 2013).

The origin of this pre-hearing spontaneous activity is still a matter of debate. It has been proposed that supporting cells within Kölliker’s organ initiate bursts of electrical activity in spiral ganglion neurons through ATP-dependent excitation of hair cells (Tritsch, Yi, Gale, Glowatzki, & Bergles, 2007). Moreover, it has been shown that ATP stimulates purinergic autoreceptors in inner spiral bundle cells, triggering Cl- efflux by opening TMEM16A Ca2+-activated Cl- channels (Wang et al., 2015). However, Johnson (Johnson et al., 2011) have further provided evidence that spontaneous action potentials are intrinsically generated by IHCs and only regulated by ATP. Although efferent input is not required to initiate this bursting activity (Tritsch et al., 2010), it modulates the bursting pattern (Johnson et al., 2011; Sendin, Bourien, Rassendren, Puel, & Nouvian, 2014), and this could be directly related to the maturation of the auditory system. High IHC intracellular Ca2+ buffering and “subsynaptic” cisterns provide efficient compartmentalization and tight control of cholinergic Ca2+ signals to prevent synaptic efferent Ca2+ spillover and cross-talk to afferent ribbon synapses (Moglie, Fuchs, Elgoyhen & Goutman, 2018). This preserves the inhibitory signature of the efferent system to ensure normal development of the auditory system. Earlier work showed that surgical lesion of the efferent nerve supply causes kittens to fail to develop normal hearing (Walsh, McGee, McFadden, & Liberman, 1998). Recent in vivo recordings in MNTB neurons from α9 knockout mice have shown no changes on average spontaneous spike rates or overall bursting activity but a modification in the temporal pattern of spontaneous spikes (Clause et al., 2014). This is translated into an impaired refinement of functional MNTB-LSO maps before the onset of hearing (Clause et al., 2014) and deficits in frequency difference limens and sound localization (Clause et al., 2017). This indicates that the precise temporal pattern of spontaneous prehearing activity is important for the formation of tonotopy in the central auditory pathway and that the transient efferent cholinergic innervation to IHCs is crucial to maintain this temporal pattern.

It is interesting to note that during AMPA-mediated excitotoxicity in the adult guinea pig cochleas, which results in swelling and disappearance of radial afferents below IHCs, vesiculated efferents (sometimes with postsynaptic cisterns) make transient direct contacts with IHCs (Ruel et al., 2007). These direct efferent contacts resemble those seen during the critical period of early stages of IHCs synaptogenesis and disappear as efferents make normal axo-dendritic synapses with the regenerated auditory neurites. Moreover, cochlear injury triggers the release of ATP and induces Ca2+ waves in supporting cells, as observed during development (Gale, Piazza, Ciubotaru, & Mammano, 2004). In addition, in aged C57BL/6 efferent terminals re-innervate IHCs, making direct synaptic contacts, containing focal presynaptic accumulations of small vesicles and occasional postsynaptic cisterns (Lauer, Fuchs, Ryugo, & Francis, 2012). Surprisingly, electrophysiological recordings from these C57BL/6J mouse IHCs reveal that functional cholinergic synaptic inputs re-emerge during aging. These efferents are inhibitory and recapitulate the same ionic mechanisms (α9 mediated-SK activation) as the transient efferent contacts present during the developmental critical period (Zachary & Fuchs, 2015). The re-appearance of efferent contacts below IHCs during damage and aging is intriguing. Since similar histological changes are seen at the level of radial dendrites between acute exposure to kainate or AMPA and those observed in various pathophysiological conditions such as ischemic events or acoustic trauma, excitotoxicity might be involved in a variety of cochlear diseases such as sudden deafness (or other ischemia-related pathologies), noise-induced hearing loss, and noise-induced tinnitus (Puel, Ruel, Gervais d'Aldin, & Pujol, 1998; Pujol & Puel, 1999; Spoendlin, 1971). If re-appearance of direct efferent contacts in IHCs were to be reported in all these conditions, a re-emergence of a developmental-like critical period could be suggested. This could be important for early therapeutic intervention in these pathological conditions, since critical periods are known to be an epoch of increased plasticity of the central nervous system (de Villers-Sidani, Simpson, Lu, Lin, & Merzenich, 2008; Levelt & Hubener, 2012; Zhou, Panizzutti, de Villers-Sidani, Madeira, & Merzenich, 2011).

Conclusions and Forward

Much progress has been made concerning the anatomy, physiology, and molecules involved in the MOC innervation to the inner ear hair cells. Plasticity features of the MOC-hair cell synapse ensure low probability of release at rest and facilitation of responses at high frequency stimulation. These are important to provide a fine tuning of cochlear amplification, since efferent firing frequency increases linearly with sound intensity. Moreover, the increase of MOC firing rate with sound intensity is consistent with the proposal that the efferent system protects the inner ear from noise-induced trauma. Future studies should provide a deeper insight on the functional roles of MOC activity in audition. The participation of the efferent innervation during the critical period and the "re-opening" of a critical period-like epoch during cochlear damage should be investigated further as a window for intervention during trauma.

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