Diverse identities and sites of action of cochlear neurotransmitters

Siân R Kitcher; Alia M Pederson; Catherine JC Weisz

doi:10.1016/j.heares.2021.108278

. Author manuscript; available in PMC: 2023 Jun 1.

Published in final edited form as: Hear Res. 2021 May 24;419:108278. doi: 10.1016/j.heares.2021.108278

Diverse identities and sites of action of cochlear neurotransmitters

Siân R Kitcher ¹, Alia M Pederson ¹, Catherine JC Weisz ^1,^*

PMCID: PMC8611113 NIHMSID: NIHMS1712087 PMID: 34108087

Abstract

Accurate encoding of acoustic stimuli requires temporally precise responses to sound integrated with cellular mechanisms that encode the complexity of stimuli over varying timescales and orders of magnitude of intensity. Sound in mammals is initially encoded in the cochlea, the peripheral hearing organ, which contains functionally specialized cells (including hair cells, afferent and efferent neurons, and a multitude of supporting cells) to allow faithful acoustic perception. To accomplish the demanding physiological requirements of hearing, the cochlea has developed synaptic arrangements that operate over different timescales, with varied strengths, and with the ability to adjust function in dynamic hearing conditions. Multiple neurotransmitters interact to support the precision and complexity of hearing. Here, we review the location of release, action, and function of neurotransmitters in the mammalian cochlea with an emphasis on recent work describing the complexity of signaling.

Introduction

Early studies of neurotransmitters in the cochlea relied predominantly on histological techniques to visualize the location of neurotransmitters, and so necessarily focused on cochlear anatomy. Advances in molecular biology techniques, genetic engineering, and physiological recordings have allowed a closer look not only at which transmitters are present in the cochlea, but also their functional roles. While up to 200 molecules can be classified as neurotransmitters (Svensson et al., 2018), here we consider molecules that have specifically been investigated in the cochlea in an update from previous, excellent reviews (Dulon et al., 2006; Eybalin, 1993; Sewell, 2011). We restrict the substances considered to those released in the cochlea with function on an acute timescale.

Glutamate

Rapid, excitatory neurotransmission throughout the central nervous system (CNS) is primarily mediated by glutamatergic signaling through ionotropic post-synaptic receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA), N-methyl-D-aspartate (NMDA), or kainate subtypes. Glutamatergic signaling generally evokes a fast (ms timescale kinetics), excitatory and depolarizing post-synaptic response, but it can also act through metabotropic receptors at pre- and post-synaptic sites with diverse downstream effects.

Glutamate release from IHCs

The inner hair cell (IHC) is the primary sensory receptor of the mammalian cochlea. It sends signals to the auditory centers of the brain through the type I spiral ganglion neurons (SGNs) of the auditory nerve (Figure 1A, B). Synapses between IHCs and type I SGNs are termed ribbon synapses after the electron dense structure, or ribbon, at the presynaptic active zone. The ribbon is associated with multivesicular release from IHCs to drive fast, large-amplitude, post-synaptic responses in type I SGNs (for review see Wichmann and Moser, 2015).

Figure 1: — Glutamate signaling in the organ of Corti. A. Schematic of the developing IHC afferent signaling complex indicating localization to cochlear cells of vesicular glutamate and proton release, receptor subtypes, and membrane transporters. Note: localization of molecules to SGN somata not depicted. Synaptoplasmic cistern (grey elongated oval) depicted in the hair cell post-synaptic domain apposed to the MOC terminal. B. Schematic of the ~mature IHC afferent signaling complex with localization of glutamate signaling molecules as in ‘A’. C. Technique for whole-cell patch-clamp recordings from type I SGN afferent boutons. DIC image depicts the recording electrode (lower right) patched onto a type I SGN post-synaptic bouton apposed to an IHC (dashed outline). Blue box indicates region depicted in schematic (inset) of patch-clamp technique. D. Amplitude histogram of PSCs recorded from a type I SGN bouton, noise amplitude indicated in grey. Inset: Overlaid spontaneous PSC waveforms recorded from a single type I SGN afferent bouton, isolated trace (far left) shows a multi-phasic EPSC (C-D modified from Glowatzki and Fuchs 2002, Nature Neuroscience, with permission). E. Schematic of afferent signaling at the mature OHC synapse indicating localization to cochlear cells of vesicular glutamate and proton release and receptor subtypes. F. Amplitude histogram of PSCs recorded from a type II SGN dendrite. Inset shows 5 overlaid spontaneous PSCs. G. DIC images depicting type II SGN dendrite recording technique. Gi. DIC image of three rows of OHCs, stereocilia visible. Gii. Lower focal plane than in Gi, some OHCs removed. Recording electrode visible patched onto a type II SGN dendrite. Giii. Same view as Gii, dendrite highlighted blue. Giv. Confocal image of a single type II SGN recording dendrite from which patch-clamp recordings were made, filled with AlexaFluor 488 hydrazide (green). Arrowhead indicates tracer artifact at recording site. White arrows indicate OHC rows. Red arrows indicate dendrite branches. DAPI in blue labels nuclei. (F-G from Weisz et al., 2009, Nature, with permission).

Glutamate has been detected in the cochlea via biochemical techniques (Godfrey et al., 1976) and implicated in IHC-type I SGN transmission by excitotoxic lesion experiments (Pujol et al., 1985). Additionally, there is histological evidence of the glutamate-aspartate transporter (GLAST) in supporting cells surrounding the IHCs and type I SGNs (Furness and Lawton, 2003; Furness and Lehre, 1997; Glowatzki et al., 2006). AMPA receptors, composed of tetramers of the subunits GluA1–4, have been found in type I SGNs (reviewed in Reijntjes and Pyott, 2016). Whole-cell patch clamp recordings from type I SGN boutons provide functional evidence of glutamatergic signaling between IHCs and type I SGNs mediated by AMPA receptors (Figure 1C, D) (Glowatzki and Fuchs, 2002). Mice lacking pre-synaptic vesicle loading of glutamate due to knockout (KO) of the vesicular glutamate transporter (VGLUT3) are protected from noise-induced loss of pre-synaptic ribbons or post-synaptic AMPA receptors (Kim et al., 2019). This finding supports the hypothesis that glutamate excitotoxicity is critical for noise-induced loss of IHC-type I SGN synapses, and likely also loss of SGN somata (reviewed in Pujol and Puel, 1999). The presence of the GluA2 subunit renders AMPA receptors calcium-impermeable (Eybalin et al., 2004), and AMPA receptors both containing and lacking GluA2 are present at mature type I SGN synapses (Hu et al., 2020; Sebe et al., 2017). The presence of GluA2-lacking AMPA receptors has not been determined at the immature type I SGN synapse. Blockade of GluA2-lacking AMPA receptors is protective against synapse loss due to noise trauma (Hu et al., 2020), which indicates that calcium entry through the calcium-permeable AMPA receptors likely mediates excitotoxic and noise-induced damage to SGNs.

Synaptic transmission through NMDA-type glutamate receptors is likely present in the cochlea, but the many contradictory data complicate efforts to detail NMDA-mediated glutamate signaling. Recordings from single, isolated spiral ganglion somata in the guinea pig (Ruel et al., 1999), or the type I SGN postsynaptic bouton in the rat (Glowatzki and Fuchs, 2002), did not show evidence that NMDA receptors substantially contributed to synaptic transmission. However, NMDA receptors are present in SGNs (Knipper et al., 1997; Lu et al., 2011; Ruel et al., 2008) and co-application of glutamate and salicylate leads to increased SGN excitability that can be prevented by NMDA antagonists. This suggests that secondary compounds can augment the response of NMDA receptors to glutamate released by IHCs (Ruel et al., 2008). More recent recordings from SGN somata suggest that NMDA receptors are critical for pre-hearing SGN maintenance (Zhang-Hooks et al., 2016). NMDA receptors may also play a role in development and synaptic repair (Ruel et al., 2007).

Similarly, kainate receptors do not appear to contribute to afferent activity (Martinez-Monedero et al., 2016; Ruel et al., 2000) or shape spontaneous excitatory post-synaptic currents (EPSCs) in vitro (Glowatzki and Fuchs, 2002). However, all five KAR subunits (GluK1–5) have been detected in afferent dendrites co-localized with GluA2 (Peppi et al., 2012)(Figure 1A, B). The compound action potential (CAP) can be reduced by cochlear perfusion of a GluK1 antagonist (Peppi et al., 2012). Post-synaptic KARs containing GluK5 and 2 have been reported at the adult IHC to type I afferent synapse, and GluK2 is also reported pre-synaptically (Fujikawa et al., 2014). No specific functional role for kainate receptors has been confirmed at the IHC-type I SGN synapse, but it is suggested that the pre-synaptic receptors could modulate neurotransmitter release, and that the post-synaptic receptors likely regulate neuronal excitability (Figure 1E) (Fujikawa et al., 2014).

The metabotropic glutamate receptor (mGluR) family consists of eight members in three groups (Lu, 2014). SGNs of guinea pig and rat express mGluR1 (Safieddine and Eybalin, 1995) and a subset show mGluR1 immunolabeling (Peng et al., 2004b). Group I (which includes mGluR1 and mGluR5) agonists induce transient inward currents (Peng et al., 2004b) and evoke action potentials (Kleinlogel et al., 1999; Peng et al., 2004b) in type I SGNs, which can be blocked by mGluR1 antagonists (Kleinlogel et al., 1999). Blocking mGluR1s in vivo had no effect on hearing threshold, but did cause a reduction in both CAP amplitude in response to loud sounds and noise-induced threshold shifts, suggesting that mGluR1 enhances cochlear responses (Peng et al., 2004b). mGluR1 has been implicated in enhancing the acetylcholine (ACh)-induced inhibition of IHCs by the transient medial olivocochlear (MOC) efferent innervation that occurs prior to hearing onset (see below), suggesting that it may also affect maturation of the ascending auditory pathway (Ye et al., 2017). Non-specific group II (mGluR2 and 3) agonists have been reported to increase dopamine release in the guinea pig cochlea via a disinhibitory mechanism in which glutamate activates mGluR2 on GABAergic, but not dopaminergic, lateral olivocochlear (LOC) efferent terminals, inhibiting tonic GABA release and thus disinhibiting dopamine release (Doleviczényi et al., 2005). This would suggest a role for mGluR2 in self-regulation of glutamate signaling via an increase in inhibitory dopamine signaling through the LOC system. However, mGluR2 has not yet been definitively localized to LOC fibers. Also, it is unclear how this mechanism would function in species in which there do not appear to be cytochemical GABAergic subgroups of LOC neurons, such as the mouse, in which all cochlear LOC fibers appear to express GABAergic markers (Maison et al., 2003a). Expression of one of the group III mGluRs, mGluR7, has been observed in IHCs, outer hair cells (OHCs) and SGNs of mice and humans (Friedman et al., 2009). Genetic variants of group III receptors have been associated with age-related hearing loss in humans (Friedman et al., 2009; Newman et al., 2012). Immunolabeling for mGluR7 localizes to efferent terminals beneath OHCs, suggesting a potential pre-synaptic role in MOC neurons (Figure 1A) (Fujikawa et al., 2014) that may inhibit neurotransmitter release via activation of Gi/Go G-proteins.

Glutamate release from OHCs

The role of OHCs in cochlear amplification is well described (Ashmore et al., 2010; Dallos, 2008), however the function of their afferent innervation of type II SGNs (Figure 1E) is unclear. The uncertainty of whether OHCs signal to type II SGNs, and if so, which neurotransmitter they use has been resolved, but the response of the type II SGNs indicates a fundamentally different function to their type I SGN counterparts.

OHCs display pre-synaptic vesicles at ribbon synapses (reviewed in Fuchs and Glowatzki, 2015), and patch-clamp capacitance recordings from immature OHCs demonstrated calcium-dependent vesicle fusion (Beurg et al., 2008), confirming the ability of OHCs to release neurotransmitter. Earlier patch-clamp recordings from type II SGN cell bodies demonstrated somatic glutamatergic currents (Jagger and Housley, 2003). Subsequent patch-clamp recordings from dendrites of type II SGNs proximal to synapses from OHCs identified glutamatergic EPSCs that were blocked by AMPA-type glutamate receptor antagonists (Figure 1F, G) (Weisz et al., 2009) and could be elicited by activation of single OHCs (Weisz et al., 2012). Recent work has shown with histology and patch-clamp electrophysiology that the calcium impermeable AMPA GluA2 receptor subunit is maintained at the type II SGN ribbon synapse into adulthood (Figure 1E) (Martinez-Monedero et al., 2016), despite initial reports that it was down-regulated after postnatal day (P)3 (Huang et al., 2012).

The functional effect of glutamate release from OHCs is weaker than from IHCs, eliciting a much smaller post-synaptic response in type II SGNs compared to type I SGNs (Figure 1D, F), despite the larger numbers of OHCs synapsing onto a type II SGN. This suggests divergent roles for type I and type II SGNs. The IHC-type I SGN synapse has large, fast post-synaptic responses that evoke action potentials with a high probability (Rutherford et al., 2012; Yi et al., 2010) to encode sound stimuli with high precision. In contrast, the OHC-type II SGN synapse is weaker. Type II SGNs may instead integrate stimuli over time or sound frequencies, and in response to loud, damaging sounds that activate the entire pool of presynaptic OHCs (reviewed in (Fuchs and Glowatzki, 2015)). Recent work demonstrates type II SGN activation by broadband sound at non-traumatic intensity levels, via glutamate release from OHCs (Weisz et al., 2021), which is consistent with activation of type II SGN by a large region of the basilar membrane. Therefore, type II SGNs likely participate in hearing during normal, non-damaging sound exposure.

Histological techniques suggest additional complexity of OHC glutamate release. Kainate receptors have been detected on type II SGNs, OHCs, and MOC efferent terminals (Figure 1E) (Fujikawa et al., 2014). This suggests varied kinetics of glutamatergic PSCs in type II SGN dendrites, although slower PSCs indicative of kainate receptor-mediated currents have not been detected (Martinez-Monedero et al., 2016). The kainate receptors on MOC terminals and OHCs suggests potential roles at both cells for glutamate spillover from the OHC-type II SGN afferent synapse. In addition, immunolabeling for the scaffolding protein Homer, associated with mGluRs (Boeckers, 2006), suggests mGluR activity at type II SGNs (Figure 1E) but at the ribbon-less, “silent” contacts adjacent to and in the same neuron as ribbon-associated contacts (Martinez-Monedero et al., 2016). The function of these synapses is currently unknown, but the “silent” contacts have been suggested as a potential substrate for synaptic plasticity.

Acetylcholine

The olivocochlear efferent neurons of the ventral brainstem innervate cells of the organ of Corti (Frank and Goodrich, 2018; Warr and Guinan, 1979), with roles in attention, adjusting cochlear gain, and protection against noise trauma via inhibition of OHC electromotility (Fuchs and Lauer, 2019). The loss of acetylcholinesterase (AChE) staining in de-efferented cochleae (Schuknecht et al., 1959, reviewed in Eybalin, 1993), demonstrates that olivocochlear neurons are cholinergic (Figure 2). ACh release from auditory efferents will only be discussed briefly because the innervation patterns, actions on hair cells, re-innervation of IHCs during aging, and functions in hearing have been recently reviewed (Fuchs and Lauer, 2019; Guinan, 2018).

Figure 2. — Cholinergic signaling in the organ of Corti. A. Schematic of the developing IHC indicating localization of vesicular ACh and proton release, receptor subtypes, markers of ACh synthesis, and key potassium channels. Synaptoplasmic cistern depicted in the hair cell post-synaptic domain opposed to the MOC terminal (grey elongated oval). B. Voltage-clamp patch-clamp recordings at different holding potentials from a second post-natal week rat IHC showing spontaneous bi-phasic responses to MOC ACh release consisting of a fast cholinergic current/depolarization followed by a slower SK potassium current/hyperpolarization. (from Glowatzki and Fuchs, 2000 Science, with permission). C. Schematic of the mature OHC efferent synapse indicating localization of vesicular ACh and proton release, receptor subtypes, markers of ACh synthesis, and key potassium channels. Synaptoplasmic cistern depicted in the hair cell post-synaptic domain opposed to the MOC terminal (grey elongated oval). D. Voltage-clamp (top) and current-clamp (bottom) patch-clamp recordings from a second post-natal week mouse OHC showing evoked PSCs (top) and PSPs (bottom) in response to electrical shocks to MOC axons. Both traces show bi-phasic responses to MOC ACh release consisting of a fast cholinergic current/depolarization followed by a slower SK potassium current/hyperpolarization (from Ballestero et al., 2011 J. Neurosci, with permission). E. Schematic of the aged IHC efferent synapse, as in ‘A’, indicating the re-emergence of olivocochlear axon terminals (LOC vs MOC not yet defined, indicated by (?)OC. F. Voltage-clamp traces from single IHCs from dissected cochleae performed at the ages indicated. High potassium application induces a slow inward current in the IHC. High potassium simultaneously stimulates pre-synaptic olivocochlear efferent terminals to release ACh and evoke PSCs in the post-synaptic IHC of developing (P7–10) and aging (8.9–9.5 months, 11–12 months) mice. PSCs are not present in young adult (1 month) mice (from Zachary and Fuchs, 2015, J. Neurosci, with permission). G. Schematic of LOC to type I SGN synapse indicating localization of vesicular ACh and proton release, receptor subtypes, and markers of ACh synthesis.

Cholinergic signaling from MOC neurons onto developing IHCs

Immature IHCs are transiently innervated by MOC efferent neurons which release ACh, activating post-synaptic heteromeric nicotinic ACh receptors composed of both α9 (Elgoyhen et al., 1994) and α10 (Elgoyhen et al., 2001) subunits (Figure 2A) (reviewed in Elgoyhen and Katz, 2012). Whole-cell patch-clamp recordings from IHCs of prehearing mice show a prolonged increase in spontaneous release from MOC terminals in response to nicotine application. Since nicotine does not activate the α9/α10 nAChR on HCs, these results suggest the presence of pre-synaptic nAChRs that facilitate MOC signaling to IHCs upon activation with ACh (Zhang et al., 2020). The α1 ACh receptors are also expressed beginning around birth in IHCs in mice, but with a currently unknown function (Roux et al., 2016). The ion flow through α9α10 ACh receptors evokes a characteristic biphasic response consisting of depolarization via the ACh receptors followed by calcium-dependent activation of SK or BK potassium channels. The SK or BK current yields a long hyperpolarization, for a net inhibitory effect on the hair cells (Figure 1B) (reviewed in Fuchs and Lauer, 2019). IHCs can generate both evoked and spontaneous calcium action potentials (Kros et al., 1998). These action potentials can be reduced in frequency or abolished by hyperpolarization resulting from exogenous ACh application (Glowatzki and Fuchs, 2000), and evoked release of ACh from efferent terminals (Goutman et al., 2005). This suggests that efferent inhibition modulates the spiking patterns of IHCs, as shown in mice during the first postnatal week (Johnson et al., 2011b; Sendin et al., 2014), as well as the patterns of activity seen in the inferior colliculus (Babola et al., 2021). The spiking activity of juvenile IHCs causes bursts of activity in type I SGNs (Glowatzki and Fuchs, 2002; Tritsch et al., 2010, 2007) and is essential for the establishment and refinement of auditory system circuitry (Clause et al., 2014; Johnson et al., 2011; Tritsch et al., 2010, 2007; Tritsch and Bergles, 2010).

Cholinergic signaling from MOC neurons onto OHCs

MOC efferent fibers use the same mechanism described above to exert rapid inhibition on OHCs and immature IHCs (Figure 2A); gating of α9/α10 ACh receptors in the basolateral hair cell membrane that leads to a characteristic biphasic response via activation of SK or BK potassium channels by the calcium influx through the α9/α10 ACh receptor (Figure 2C) (Wersinger and Fuchs, 2011). OHCs develop this response over the first two postnatal weeks in rodents (Roux et al., 2011). The MOC reflex is proposed to inhibit cochlear amplification by OHCs via this cholinergic synapse onto OHCs (Figure 2D) (Fuchs and Lauer, 2019).

Cholinergic reinnervation of IHCs in aging

In the aging cochlea, efferent synapses onto IHCs re-emerge (Figure 2E), demonstrated by the appearance of efferent terminals making synaptic contacts with an immature morphology (Lauer et al., 2012). The C57BL/6J mice used for these studies have early-onset age-related hearing loss with degeneration of afferent synapses due to a mutation in cadherin 23 (Noben-Trauth et al., 2003; Stamataki et al., 2006), a major component of stereocilia tip-links (Siemens et al., 2004). Voltage-clamp recordings from the re-innervated IHCs confirm that the efferent synapses are cholinergic and inhibit the IHC via SK potassium channels, similar to the developing efferent synapse (Figure 2F, G) (Zachary and Fuchs, 2015). This efferent reinnervation of IHCs is coincident with several auditory pathologies including elevated ABR thresholds, fewer afferent synapses per IHC, increased OHC loss (Lauer et al., 2012) and ribbon loss (Zachary and Fuchs, 2015), though a causal relationship between the auditory pathology and re-innervation has not been determined. It is currently unknown whether the cholinergic re-innervation is from LOC or MOC fibers. It has previously been shown that C57BL/6J mice experience an age-related loss of MOC terminals contacting OHCs (Fu et al., 2010). It is then possible that after the deterioration of the MOC-OHC synapse, the MOC fibers retract back to innervate IHCs (Lauer et al., 2012). However, LOC efferents do innervate type I afferent fibers very close to the basal pole of the IHC, so in the event of lost afferent innervation, LOC fibers are ideally situated to re-target IHCs (Zachary and Fuchs, 2015). The function of the emergent efferent synapse is also unknown; it could be protective against further cochlear pathology by limiting IHC activity and subsequent excitotoxicity. The efferent fibers could also offer trophic support to remaining afferent fibers. The latter suggestion is consistent with the observation that the loss of afferent fibers in C57BL/6J mice preferentially occurs on the same side of the IHC as the efferent reinnervation (Lauer et al., 2012; Stamataki et al., 2006). Conversely, the reinnervation could be detrimental to hearing by suppressing IHC responses to normal levels of sound. Discovery of markers specific to LOC or MOC fibers will help to determine which cell type is innervating IHCs and will yield genetic tools to allow selective enhancement or elimination of reinnervation to further investigate its function.

Cholinergic signaling from LOC neurons

Somata of LOC efferent neurons projecting to the cochlea are located in the ventral brainstem within and immediately surrounding the lateral superior olive (LSO). Cholinergic markers including AChE, the synthesis enzyme choline acetyltransferase (ChAT), and the vesicular acetylcholine transporter (VAT) distinguish LOC efferent neurons from LSO principal afferent neurons that are implicated in sound localization (Darrow et al., 2007; Eybalin, 1993; Eybalin and Pujol, 1987; Felix and Ehrenberger, 1992; Maison et al., 2003a; Ruel et al., 2007; Safieddine et al., 1997; Safieddine and Eybalin, 1992; Sobkowicz and Emmerling, 1989; Vetter et al., 2007). The anatomy of LOC neurons has also been recently reviewed (Fuchs and Lauer, 2019), but it is unclear whether these anatomical groupings of LOC neurons are neurochemically distinct, as different methods describe differential expression of markers for dopamine, GABA, CGRP, enkephalins, and other neurotransmitters (see relevant sections).

Unlike in the MOC system, ACh exerts a net excitatory effect on the LOC neuron’s post-synaptic partner, the type I SGN neuron (Felix and Ehrenberger, 1992, 1982), which is attributed to the actions of muscarinic ACh receptors on type I SGN activity (Figure 2G) (Ito and Dulon, 2002; Maison et al., 2010b). The type I SGN spike initiation zone is located at the habenula perforata, which is very close (~20–40 μm) to the IHC-type I SGN synapse and has a high density of voltage-gated sodium channels to support action potential initiation (Hossain et al., 2005; Kim and Rutherford, 2016). The LOC neurons form synapses onto the type I SGN just peripheral to this region between the IHC and the habenula perforata, and so are ideally positioned to regulate type I SGN action potentials by modulating sodium channel activity or intrinsic electrical properties of the afferent fiber. In addition to receptor localization to SGN peripheral fibers post-synaptic to LOC neurons, immunohistochemistry suggests the presence of muscarinic receptors, specifically M2 mAChRs, on olivocochlear efferents in the IHC and OHC areas. This suggests that mAChRs may also play a role as pre-synaptic autoreceptors on efferent axon terminals (Maison et al., 2010b). Because LOC neurons may release a variety of neurotransmitters and peptides (described below), the effect of LOC neurons on hearing is varied and complex, causing both excitation and inhibition of various measures of cochlear function (Groff and Liberman, 2003).

GABA

Gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter of the central nervous system (Roberts and Kuriyama, 1968) and as such was a potential candidate for inducing the reduction of the CAP seen upon efferent fiber stimulation (Galambos, 1956). Although acetylcholine was instead later found to be the primary neurotransmitter of the MOC system, evidence of GABA in the cochlea was found (Fex and Wenthold, 1976; Godfrey et al., 1976).

The OC efferent system is the only reported source of GABAergic input to the mammalian cochlea (Figure 3A)(Maison et al., 2009). Both LOC and MOC neurons are GABAergic with significant, and perhaps complete, overlap with cholinergic OC fibers. The broad cochlear innervation by efferent neurons and presence of receptors in multiple cell types suggests complex potential functions for GABA in the cochlea.

LOC efferent neurons are likely GABAergic and cholinergic. In guinea pig, radioactive GABA and markers of GABA and/or GABAergic activity have been localized to both lateral and medial components of the OC efferent system (Eybalin et al., 1988; Fex et al., 1986; Fex and Altschuler, 1984; Gulley et al., 1979). In the guinea pig ISB GABA- or GAD-like immunoreactivity peaks in the third turn (Eybalin et al., 1988; Fex et al., 1986; Fex and Altschuler, 1984), but is reported as appearing in the middle of the basal (Fex et al., 1986) or second turn (Fex and Altschuler, 1984), or to be present throughout all turns (Eybalin et al., 1988). In the ISB of mouse (Maison et al., 2003a; Nitecka and Sobkowicz, 1996), rat (Merchán-Pérez et al., 1993; Vetter et al., 1991), squirrel monkey (Thompson et al., 1986), and human (Schrott-Fischer et al., 2002), evidence of GABAergic innervation was localized along the whole length of the cochlear spiral.

In the OSB and specifically MOC terminals onto OHCs, GABAergic markers appear in the second cochlear turn and peak in the third turn of the guinea pig cochlea (Eybalin et al., 1988; Eybalin and Altschuler, 1990; Fex et al., 1986; Fex and Altschuler, 1984). In rat and mouse there are conflicting reports of GABA localization, with some studies finding evidence of GABAergic fibers only in the more apical turns (Merchán-Pérez et al., 1993; Vetter et al., 1991) and others reporting evidence of GABAergic fibers along the whole length of the cochlea (Dannhof et al., 1991; Maison et al., 2003a). The latter results are consistent with the patterns found in primates; both squirrel monkeys (Thompson et al., 1986) and humans (Schrott-Fischer et al., 2002) have GABAergic terminals contacting OHCs throughout all cochlear turns.

Whether GABAergic efferent fibers represent a subpopulation of the efferent system or whether GABA is found in all efferents appears to vary across species. Even in the cochlear areas of maximal GABA immunoreactivity in guinea pig, half or more of the fibers visualized in both the ISB and OSB are unstained, suggesting that GABAergic efferent fibers constitute a subpopulation of neurons (Eybalin et al., 1988; Fex et al., 1986; Fex and Altschuler, 1984). In contrast, staining of all MOC fibers or terminals has been reported in human (Schrott-Fischer et al., 2002), rat (Dannhof et al., 1991) and mouse (Maison et al., 2003a), with the latter study showing 100% co-localization of GAD and VAT staining to confirm that all cholinergic efferent MOCs co-express GABA. Interestingly, the same study found more GAD-positive terminals compared to VAT-positive terminals in LOC fibers of the apical cochlea, however this could be due to lower immunostaining intensity for VAT (Maison et al., 2003a), and still suggests that no GABAergic subgroup exists. Studies investigating additional cochlear neurotransmitters, such as dopamine and serotonin (see below), suggest that signaling between LOC neurons from different sub-populations as defined by GABA expression is critical for some aspects of these other neurotransmitters’ functions. However, these complex interactions between neurotransmitter systems may need to be reconsidered in species that may not have clear distinctions between LOC neuron subpopulations.

GABAergic signaling may play a role in development of the auditory system, with one proposed mechanism acting via GABA B receptors. GABA B receptors are G-protein coupled receptors composed of two subunits, GABA B1 and GABA B2, and are expressed in SGNs (Lin et al., 2000). The GABA B1 receptor subunit is necessary for functional GABA B receptors (Prosser et al., 2001; Schuler et al., 2001). The GABA B1 subunit is not observed in the hair cells of adult (Maison et al., 2009) or juvenile (Wedemeyer et al., 2013) mice. Instead, GABA B1 has been observed around the onset of hearing in the IHC and OHC areas in both efferent and afferent fibers, using mice expressing GFP-tagged GABA B1 subunits (Wedemeyer et al., 2013). Patch-clamp experiments were performed from either developing mouse IHCs or from OHCs shortly after hearing onset, during the stages when each hair cell type is innervated by MOC terminals (Figure 3B, E). GABA inhibits ACh release from MOC efferents at both synapses by activating presynaptic GABA B receptors located on the MOC axon terminal (Figure 3C–D, F–G), confirmed to contain the GB1a isoform at the IHC-MOC synapse (Wedemeyer et al., 2013). These experiments propose a physiological role for GABA in feedback inhibition of efferent transmission. In adult mice, GABA B1 Rs are no longer seen in the efferent fibers and deletion of this subunit does not affect the MOC efferent suppression of OHC activity (Maison et al., 2009). GABA signaling through the B1 receptor in efferent fibers regulates the strength of the MOC-IHC synapse in a critical developmental period (Wedemeyer et al., 2013), during which the spiking activity of IHCs is thought to drive circuit development in higher auditory nuclei (Clause et al., 2014), and so likely has a role in development of auditory circuits.

GABA signaling has been implicated in maintenance of cochlear structures through activation of both metabotropic GABA B receptors, described above, and GABA A receptors. Ionotropic GABA A receptors are ligand-gated chloride channels composed of 5 subunits with diverse receptor composition (Goetz et al., 2007). PCR experiments have identified the GABA A α_1–6, β_1–3 and γ₂ subunits in the cochlea of (P)14–18 mice (Drescher et al., 1993). Mice with systemic knockouts of GABA A receptor subunits α1, α2, and α6 show no cochlear histopathology or auditory function deficits into adulthood (Maison et al., 2006). This suggests that these subunits are not integral for hair cell or neuron function or development, although compensation by other GABA A subunits is possible (Kralic et al., 2002). Mice with systemic knockouts of either the GABA A receptor subunits α5, β2, β3 (Maison et al., 2006), or metabotropic GABA B1 receptor subunits (Maison et al., 2009) do not initially have increased OHC loss compared to WT, but do exhibit elevations of DPOAE and ABR thresholds. The increases in threshold for both measurements were similar, suggesting dysfunction of the OHCs that impairs their role in cochlear amplification (Maison et al., 2009, 2006). As they age, the GABA A receptor α5 and β2 subunit knockout animals have ABR shifts that are significantly larger than the DPOAE shifts, suggesting a progressive dysfunction in afferent neuron or IHC function. All three GABA A receptor mutants also show progressive loss of IHCs and OHCs in the basal 15% of the cochlea, loss of afferent fibers where IHCs are also lost, and reduced efferent innervation of OHCs throughout the cochlea. In α5 and β2 subunit KO animals, efferent innervation develops normally, and its deterioration occurs at varying ages of onset depending on which receptor subunit is missing (Maison et al., 2006). The broad range of abnormalities seen in the GABA A receptor subunit knockouts suggests multiple sites of GABA action through GABA A receptors in the cochlea, and potentially distinct roles for receptors composed of different GABA A subunit complements. These results suggest roles for GABA in the long-term maintenance of both IHC and OHC, and the efferent and afferent neurons of the cochlea. However, interplay between peripheral and central circuitry may also be involved in deficits seen in GABA receptor knockout animals. The MOC synapse onto developing IHCs is critical for development of afferent circuitry (Clause et al., 2014). Further, inhibitory synapses from the ascending medial nucleus of the trapezoid body (MNTB) have been found on LOC (Sterenborg et al., 2010) and MOC neurons in the brainstem (Torres Cadenas et al., 2020), suggesting that both MOC and LOC somatic function may be disrupted by systemic GABA receptor KOs. Nonetheless, GABA receptor knockout experiments do demonstrate important roles for GABA in auditory function, cochlear morphology, and cellular maintenance.

It is currently unclear what the acute effects of GABA A receptor signaling are on hair cell function because the systemic knockouts described above affect survival of cochlear cells and possible changes to central circuitry, but studies suggest a potential for GABAergic signaling during normal hearing conditions. In adult guinea pig, α and β subunits were detected at the basal pole of isolated OHCs, but not IHCs (Plinkert et al., 1989). Hyperpolarization (Gitter and Zenner, 1992; Plinkert et al., 1993) and changes in motility (Batta et al., 2004; Plinkert et al., 1993) induced by exogenous GABA application, and blocked by GABA A antagonists, have been reported in isolated OHCs of adult guinea pigs. Diffuse immunostaining for the β2 and β3 subunits has been observed in mouse OHCs in the cochlear apex (Maison et al., 2006) but no effect of GABA is seen in OHCs (or IHCs) of dissected whole cochlear preparations of (P)9–16 mice (Wedemeyer et al., 2013). Thus, the action of GABA A receptors on OHCs is still unclear.

GABA may also play a modulatory role in SGN afferent signaling. In vivo extracellular recordings in the IHC dendritic region revealed little effect of iontophoresed GABA on the spontaneous firing rates of afferent fibers. However, GABA application inhibits ACh- or glutamate-evoked type I SGN activity (Arnold et al., 1998; Felix and Ehrenberger, 1992), likely through GABA A receptors (Arnold et al., 1998). These results suggest that GABA release may reduce auditory nerve activity but through an unknown mechanism. GABA A receptor subunit β3 immunolocalizes to SGN and subunits β2/3 also immunolocalize beneath IHCs (Maison et al., 2006), likely on type I SGN, indicating that GABA may be released from LOC axon terminals onto type I SGN peripheral processes. Indeed, whole-cell patch-clamp recordings from SGNs isolated from embryonic day (E)14-(P)5 mice display chloride currents after exogenous GABA application, which are blocked by the GABA A-specific antagonist bicuculline (Lin et al., 2000). In the guinea pig cochlea, GABA A receptors have been proposed to play a role in disinhibition pathways whereby tonic GABA release from GABAergic LOCs is inhibited by mGluR (Doleviczényi et al., 2005) or 5-HT₆ /5-HT₇ receptor activation (Doleviczényi et al., 2008), allowing an increase of DA release from dopaminergic LOCs. This implies that that GABA A receptors are located on a subpopulation of GABAergic LOC terminals, however, this mechanism may not apply to other species where GABAergic subgroups of LOC may not exist (Maison et al., 2003a).

GABA may also have a role in protection against noise trauma. Vulnerability to permanent, but not temporary, acoustic injury is decreased in GABA B1 KO mice suggesting that GABAergic signaling may play a role in the processes triggered by acoustic trauma. In adult mice, GABA B1 receptors are no longer immunolocalized to efferent terminals but can be immunolocalized to the synaptic terminals of both type I and type II SGN (Maison et al., 2009). This receptor localization suggests GABAergic signaling in both SGN types into adulthood, likely from the olivocochlear efferent system. However, this was a systemic knockout of the GABA B1 receptor, and developmental processes at IHCs, OHCs, or other cell types may also have been subtly altered.

Despite being demonstrated to be present in only the olivocochlear efferent system, GABA plays many roles in the cochlea which appear to be governed by careful timing and location of receptor expression as well as receptor subunit composition. GABA B receptors likely aid auditory circuitry development by inhibiting ACh release. GABA A receptors also possibly modulate the release of other neurotransmitters and have roles in the maintenance of HCs, efferent fibers, and afferent fibers. Both receptor subfamilies are involved in normal hearing function, evidenced by functional deficits after systemic KO, however future work using cell type-specific mutations or inducible knockouts may be needed to separate of the roles of GABA in peripheral vs central circuits, and in development vs the mature system.

Glycine

Glycine is one of the primary inhibitory neurotransmitters in the central nervous system and has been detected in the cochlea in numerous studies (reviewed in (Eybalin, 1993)). However, a precise role for glycine activity in the cochlea has not been determined. This is in part because the commonly used glycine receptor (GlyR) blocker strychnine is also a potent antagonist of the α9/α10 ACh receptors that mediate MOC efferent activity on hair cells (Kujawa et al., 1993; Sewell, 2011; Sridhar et al., 1995), which confounds effects. Despite this experimental limitation, more recent work indicates a possible role for glycine in cochlear efferent function using expression and protein localization studies of GlyRs and the GlyR anchoring protein gephyrin. Prior to hearing onset GlyRs localize to the base of IHCs, likely post-synaptic to MOC axon terminals that transiently innervate IHCs. After hearing onset, GlyRs localize both to the base of OHCs, likely post-synaptic to MOC axon terminals, and also to puncta below IHCs that suggest a localization on type I SGN peripheral fibers post-synaptic to LOC efferents (Buerbank et al., 2011; Dlugaiczyk et al., 2008). GlyRα2 is the predominant isoform before hearing onset and GlyRα3 is the predominant isoform after hearing onset, with some early expression of GlyRα1 (Buerbank et al., 2011). GlyRs also localize to SGN somata (Buerbank et al., 2011; Dlugaiczyk et al., 2008), and exogenous glycine evokes GlyR-mediated currents in cultured SGN somata (Sun and Salvi, 2009).

Glycine receptor knockout studies suggest glycine function in the cochlea, with possible interactions with glycinergic circuitry in the auditory brainstem. Mice with a knockout of the GlyRα3 subunit had normal wave I ABR thresholds but were more susceptible to noise trauma (Dlugaiczyk et al., 2016) and have impaired detection of signals in noise (Tziridis et al., 2017). Together these results suggest that OHCs have normal function, but that the MOC synapse onto OHCs that provides some protection against noise-induced trauma is impaired. However, the knockout of GlyRα3 in both studies was systemic and likely impaired central processing throughout the superior olivary complex (SOC). Indeed, LOC (Sterenborg et al., 2010) and MOC (Torres Cadenas et al., 2020) somata in the brainstem receive glycinergic synaptic inputs, and the GlyRα3 deficient mice also showed ABR deficits in wave III and IV suggesting aberrant signaling in the SOC (Tziridis et al., 2017). Nonetheless, GlyR localization and hearing deficits in GlyRα3 mice suggest that glycinergic signaling is implicated in MOC and possibly LOC efferent circuitry function, with potential interactions between cochlear and SOC mechanisms that have yet to be characterized.

Purines

The majority of known purine receptors are present in the cochlea, in a wide variety of cell types (reviewed in Köles et al., 2019), however the location, conditions and functional effects of purine release are not completely understood. P2X receptors are ionotropic and primarily activated by ATP (reviewed in North, 2016). P2Y receptors are metabotropic and the different subtypes are activated by the pyrimidine UTP, ATP, or the ATP metabolite ADP, alone or in combination (reviewed in von Kügelgen and Hoffmann, 2016). Purinergic receptors are localized to the organ of Corti and afferent neurons, however it is unclear whether extracellular purines in the cochlea have functions during exposure to normal levels of sound. P2X2 receptor subunits have been immunohistochemically mapped to the synaptic regions beneath OHCs and IHCs (Järlebark et al., 2000) and more specifically, to the post-synaptic density of type I and type II SGNs (Housley et al., 1999), although vesicular release of ATP from hair cells has not been documented. P2Y receptor subunits have been localized to various cells of the organ of Corti, including SGNs, which express all five subunits into adulthood (Huang et al., 2010). Exogenously applied ATP causes excitation of SGNs via two mechanisms; a direct depolarization of type I (Ito and Dulon, 2002) and type II afferent fibers (Liu et al., 2015; Weisz et al., 2009), as well as excitation of OHCs that causes them to release glutamate (Weisz et al., 2009).

The role of purines in responses to high intensity sounds have been documented. In some circumstances purine release may be protective against noise trauma; upon sound exposure, ATP levels increase in endolymph (Housley et al., 2013; Muñoz et al., 2001) and activate ionotropic P2X2 receptors in cells lining the endolymphatic space (Housley et al., 2013). P2X2 receptor activation leads to an electrical shunt as potassium diffuses out of the endolymph reducing the endocochlear potential and, in turn, cochlear sensitivity (Thorne et al., 2004). The direct excitation of OHCs by purines may also be involved in this protective response, as OHC depolarization by ATP (Nakagawa et al., 1990) renders them less responsive to sound and hinders their role in cochlear amplification (Thorne et al., 2004). Purines are also involved in cochlear responses to sounds that are loud enough to cause cellular damage. Rupturing OHCs to mimic cochlear trauma causes type II SGN depolarization mediated by both P2X and P2Y receptors (Liu et al., 2015), and P2Y receptor-mediated calcium waves are evoked in supporting cells by laser ablation of OHCs (Gale et al., 2004). Purines may also mediate the responses of type II SGN signaling to the cochlear nucleus (CN) in mice lacking cochlear glutamate release, in response to noxious sound levels (Flores et al., 2015).

Purines also have roles in the activity seen in the pre-hearing cochlea. IHCs are known to produce spontaneous calcium spikes before hearing onset (Kros et al., 1998; Marcotti et al., 2003), leading to glutamate release from the hair cells and subsequent synaptic activation of type I SGNs (Beutner and Moser, 2001; Glowatzki and Fuchs, 2002). This patterned activity has been observed in the MNTB (Tritsch et al., 2010) and the inferior colliculus (Babola et al., 2021, 2020) and is thought to drive circuit development to set the stage for later sensory input. Recent work has shown that spontaneous release of ATP from inner supporting cells (ISCs) leads to activation of P2RY1 autoreceptors on the ISCs (Babola et al., 2020). This leads to calcium spikes, chloride efflux through TMEM16A channels, and subsequent efflux of water and potassium (Wang et al., 2015). This local rise in extracellular potassium leads to depolarization of the nearby IHCs (Wang et al., 2015) and subsequent glutamate release, which induces bursting activity in SGNs (Tritsch and Bergles, 2010). While it is clear that ISCs play a role in initiating spiking in juvenile IHCs, it is not yet clear whether the specific pattern of activity is generated by an inhibition of continuous calcium spiking (Johnson et al., 2011a) or external stimulation of the IHCs (Babola et al., 2020; Wang et al., 2015) (reviewed in Wang and Bergles, 2015).

While purinergic signaling is implicated in cochlear damage and development of auditory pathways, identification of ATP as a neurotransmitter is ambiguous due to the lack of defined pre-synaptic release. However, the full spectrum of purinergic release and signaling is likely incompletely characterized, including the potential for co-release with other neurotransmitters.

Catecholamines

Dopamine

Dopamine (DA) markers have been localized to components of the afferent and efferent systems in the cochlea (Figure 4A). Localization of dopaminergic markers to LOC neurons (Figure 4B), which are characterized as primarily cholinergic, has been well documented (see Gil-Loyzaga, 1995; Lendvai et al., 2011 for reviews). LOC neurons can be separated into two distinct groups based on the location of their somata and their innervation of the cochlea. The somata of ‘shell’ neurons are found in the area surrounding the LSO (Vetter and Mugnaini, 1992) and their axons generally bifurcate upon entry to the organ of Corti (Warr et al., 1997). The somata of ‘intrinsic’ neurons are found within the LSO, and their axons tend to travel in one direction along the organ of Corti (Warr et al., 1997).

In mice, a subset of LOC efferent fibers that likely correspond predominantly to ‘shell’ neurons label for the dopamine synthesis enzyme tyrosine hydroxylase (TH) and not for ACh. Only a small proportion of the ‘intrinsic’ LOC fibers within the LSO are TH positive (Darrow et al., 2006). However, in guinea pig and rat, dopaminergic and cholinergic markers show almost complete co-localization, suggesting a single population of DA- and ACh-positive fibers (Safieddine et al., 1997).

Gene expression of all 5 DA receptors has been detected in the modiolar tissue of adult rats using PCR (Inoue et al., 2006), and D2 and D3 receptors have been detected in whole cochlea samples of adult mice using qPCR (Karadaghy et al., 1997). RT-PCR analysis on whole adult mouse cochleae showed higher expression levels for D2 receptors compared to D1, D5 and D4 receptors, and in contrast to above results, found no expression of D3 receptors in pre-hearing or mature mice (Maison et al., 2012). Also in mice, individual KO of DA receptors 1–5 did not cause abnormalities in gross cochlear morphology. D3–5 receptor KOs did not have changes in ABR or DPOAE thresholds, indicating no functional effects of these receptor knockouts. However, D1 and D2-nulls did have mildly altered auditory function in opposite directions: in D1 mutants, ABR and DPOAE responses were slightly enhanced, while in D2 mutants they were slightly attenuated (Maison et al., 2012). Of note, D2-antagonists raise CAP threshold in guinea pigs (Wang et al., 2014) but application of dopamine (Ruel et al., 2001), D2/3 DA receptor agonists (D’Aldin et al., 1995a, 1995b) and D1/5 agonists (Garrett et al., 2011) leads to a reduction in CAP amplitude. The reason for the discrepancies between studies of D2 receptor pharmacology have not been determined, but these results suggest that DA can dynamically regulate normal hearing function.

Studies of dopamine receptors indicate direct action on SGNs (Figure 4C). SGNs of the rat show immunoreactivity of all five DA receptor types (Inoue et al., 2006). In mice, D1 and D2 receptors have been immunolocalized to the ISB, closely associated with OC terminals, and to type I SGNs near the region of the first node of Ranvier (Maison et al., 2012). In keeping with these findings, in vivo cochlear perfusion of dopamine has been shown to reduce spontaneous and sound-driven activity of type I afferent fibers (Ruel et al., 2001), as does pharmacological inhibition of the dopamine transporter (DAT), which is responsible for the reuptake of DA from the synaptic cleft (Ruel et al., 2006). Whole-cell patch-clamp recordings from cultured rat SGNs show that DA receptor activation leads to a reduction in sodium current amplitude, causing a reduction in SGN excitability. This reduction in sodium current amplitude is the result of phosphorylation of voltage-gated sodium channels through both D1 and D2 mediated pathways acting via the Gαs/AC/cAMP/PKA and Gαq/PLC/PKC pathways, respectively (Valdés-Baizabal et al., 2015). Activation of the D1 receptor has also been shown to lead to phosphorylation of GluA1-containing AMPA receptors via PKA (Niu and Canlon, 2006), suggesting that dopamine may act on type I SGNs through second messenger cascades. Recordings from type I afferent boutons in post-hearing onset rats found that dopamine application significantly reduces spike rates in ANFs. EPSC amplitude and charge are reduced in the presence of DA and likely lead to the reduction of APs (Wu et al., 2020). Interestingly, application of dopamine also reduces the rate of release from IHCs, suggesting that DA acts pre- as well as post-synaptically to reduce ANF firing (Wu et al., 2020).

Dopaminergic modulation of auditory nerve activity may play a role in protection against excitotoxic injury as application of the D2/D3 agonist piribedil has also been shown to reduce the swelling seen in type I afferent terminals induced by periods of ischemia (D’Aldin et al., 1995b, 1995a) or acoustic trauma (D’Aldin et al., 1995b). In guinea pig, sound pre-conditioning leads to increased TH expression in LOC neurons and protects against ABR shifts generated by acoustic trauma, an effect that is blocked when TH expression is disrupted (Niu and Canlon, 2002). However, acoustic trauma alone causes a decrease in TH expression in the LOC fibers of the cochlea (Niu and Canlon, 2002) as well as LOC somata located in the LSO and the surrounding dorsolateral periolivary nucleus (Niu et al., 2004). Conversely, in mice it has been shown that noise trauma that increases ABR thresholds can induce TH expression in ‘intrinsic’ LOC neurons that were TH-negative prior to noise exposure. Both the ABR threshold shift and induced TH expression partially recover to control levels after three weeks (Wu et al., 2020). Together these findings suggest that acoustic experience can dynamically regulate dopaminergic input to auditory nerve fibers (Wu et al., 2020), but leave unresolved the discrepancies seen between LOC subgroups and responses to acoustic trauma between the two species.

Mice with specific dopamine receptor KOs also support a protective role for DA in the cochlea. Mice lacking D4 or D5 receptors show an increased shift in ABR, but not DPOAE thresholds in response to exposure to loud sounds, suggesting that these receptor types offer protection against noise trauma at the level of the type I afferent fibers. Interestingly, D2 KO mice show an increased shift in both ABR and DPOAE thresholds, suggesting protection at the level of the OHCs (Maison et al., 2012). Expression of D1, D2 and D5 receptors in isolated OHCs of p11–13 WT mice has been shown using RT-PCR (Maison et al., 2012).

In the OSB, weak labelling for the dopamine transporter (DAT) has been found near Deiters cells (Ruel et al., 2006). Consistent with this, type II SGN dendrites were also labeled in cochleae from mice expressing Cre recombinase driven by either the TH promoter or the Drd2 dopamine receptor promoter crossed with EYFP-expressing reporter mouse lines (Vyas et al., 2019, 2017; Wu et al., 2018). However, some cells that express TH do so only transiently, and do not release dopamine (reviewed in Björklund and Dunnett, 2007; Ungless and Grace, 2012), including some type I SGN that express TH around hearing onset but do not express other makers of dopamine synthesis (Trigueiros-Cunha et al., 2003). Release of dopamine from type II SGNs, or a post-synaptic target, has not been documented.

Noradrenaline / adrenaline

The role of noradrenaline (NA) in cochlear blood flow is well described, but the localization of adrenergic receptors to the organ of Corti including neuronal processes also suggests a possible role in afferent neuron function. Adrenergic receptors (AR), specifically α₁-AR, β₁-AR, and β₂-AR, have been immunolocalized to many structures in the cochlea. Labeling has been observed in neuronal fibers under IHCs and OHCs, SGN somata (especially in the basal turn of the cochlea), and also in Hensen and Dieters supporting cells (Khan et al., 2007). The α₂-ARs have a wide distribution in the cochlea throughout organ of Corti and spiral ganglion, as well as many non-sensory regions (Cai et al., 2013). Sympathetic neurons have broad innervation in the cochlea (Maison et al., 2010a) and are the likely source of cochlear NA, but sympathetic neurons are not known to synapse on hair cells or SGNs. Exogenous NA application does not increase calcium responses in isolated OHCs (Ikeda et al., 1991). However, NA application to isolated, cultured rat SGN neurons can act via α₂-ARs to decrease responses to co-applied GABA (Zha et al., 2007), suggesting that NA can modulate efferent innervation of afferent neurons. However, despite the broad expression of adrenergic receptors, mice with a knockout of the gene for DBH, a required enzyme for synthesis of adrenaline and NA, had normal cochlear function and unaltered susceptibility to acoustic trauma (Maison et al., 2010a). Thus, it is unclear if, and under what conditions, NA released from sympathetic neurons could diffuse to distant adrenergic receptors on sensory cells to impact hearing.

The role of catecholamines including dopamine and noradrenaline in the cochlea are difficult to dissect due to their likely release from cells that produce many other neuroactive substances. However, recent work has brought new attention to important roles of catecholamines in cochlear functions such as responses to noise trauma.

Serotonin

Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter, is widely known as a mediator of depression and anxiety in the brain, as well as performing a variety of diverse functions in the gut and peripheral nervous system (Berger et al., 2009). HPLC studies have also detected serotonin in cochlear tissue. HPLC of cochlear homogenates shows a rise in 5-HT concentration in adult rat cochleae after treatment with a selective serotonin reuptake inhibitor, suggesting synaptic serotonergic activity (Vicente-Torres et al., 2003). However, concentrations as detected by HPLC were not altered by noise exposure (Gil-Loyzaga et al., 2000). An antibody against 5-HT in the cat (Gil-Loyzaga et al., 1997) and rat (Gil-Loyzaga et al., 2000) labeled efferent neurons that spiral in the ISB and project to the OSB to form en passant synapses, although the synaptic targets in the cochlea or source of the axons in the brainstem were not determined (Gil-Loyzaga et al., 2000). Serotonin receptor subtypes 1A, 1B, 2B, 2C, 3, 5B, and 6 have been detected in the mouse and rat cochlea using RT-PCR (Oh et al., 1999). Immunolabeling against the serotonin reuptake transporter (SERT) was also transiently detected in cochlear tissue of marmoset embryos (Lebrand et al., 2006). This phenomenon has been observed in other non-serotoninergic neurons which have the capacity to uptake 5-HT released from 5-HT-synthesizing neurons during gestation, but do not synthesize 5-HT themselves (Lebrand et al., 2006).

Recently, transgenic mouse lines have been used to identify subpopulations of SGNs, including those displaying markers of serotonergic signaling. A mouse line expressing the gene for green fluorescent protein (GFP) under the control of the slc6a4 (SERT) promoter (slc6a4-GFP mice) exhibit selective labeling of most type II SGNs, as well as platelets and non-neuronal cells in the stria vascularis. Slc6a-4GFP fluorescence was localized to type II SGNs in both pre-hearing and young adult hearing mice across all tonotopic regions, but with the greatest density of labeled neurons in the middle cochlear turn. Interestingly, a similar BAC transgenic mouse line expressing Cre recombinase driven by the slc6a4 promotor (slc6a4^Cre) crossed to the Ai9 tdTomato reporter mouse line labeled both type I and type II SGN as well as efferent neurons (Vyas et al., 2019). However, Cre expression in transgenic mouse lines does not necessarily faithfully reproduce expression patterns of the gene of interest (Schmidt et al., 2013). This study suggests slc6a4-GFP mice as possible tools for studies of type II SGNs, and slc6a4^Cre mice as tools for study of both afferent and efferent neurons, but does not demonstrate serotonin release from SGNs.

While little about the function of serotonergic signaling in the cochlea is currently known, it is potentially involved with LOC dopaminergic signaling and may have a role in cochlear protection. An antagonist for the 5-HT₆ and 5-HT₇ metabotropic receptors has been shown to increase the release of dopamine in the absence of electric field stimulation in a cochlear in vitro microvolume superfusion preparation. The authors speculate that this occurs through proposed 5-HT inhibition of GABA release from LOC efferent fibers (Doleviczényi et al., 2008). Systemic pretreatment with an agonist for the ionotropic 5-HT_3A receptor enhances cochlear protection from noise damage in mice (Ohata et al., 2021), although this could be due to activity within the brainstem at MOC somata. Furthermore, systemic knockout of the 5-HT_3A receptor increases ABR threshold shifts and loss of postsynaptic receptors after noise damage, a result that can be replicated in WT mice pretreated with a 5-HT_3A antagonist (Ohata et al., 2021). Taken together, these results suggest that both metabotropic and ionotropic 5-HT receptors have a functional role in the cochlea. As many drugs targeting 5-HT receptors already exist, a deeper functional understanding of serotonin signaling in the cochlea could lead to rapid translation towards clinical therapies to treat and prevent hearing loss.

Nitric Oxide

A variety of histological techniques have localized nitric oxide (NO) signaling by revealing markers for variants of the NO synthesis enzyme nitric oxide synthase (NOS) throughout the cochlea. Type I NOS (also known as neuronal NOS or nNOS (reviewed in Förstermann and Sessa, 2012)) and Type II NOS (inducible or iNOS) have been found in the cytoplasm of, and nerve endings beneath, OHCs (Franz et al., 1996; Heinrich et al., 1997) and IHCs (Heinrich et al., 1997). Type I and Type II NOS have also been found in SGN cell bodies and fibers projecting to the cochlea as well as the brainstem, supporting cells, the lateral wall, tunnel crossing fibers, and the stria vascularis (Fessenden et al., 1994; Franz et al., 1996; Heinrich et al., 1997). NOS III (also known as epithelial NOS, eNOS (reviewed in Förstermann and Sessa, 2012)) reactivity has also been documented in the cytoplasm of OHCs (Franz et al., 1996) and IHCs (Heinrich et al., 1997), the stria vascularis, and the spiral limbus (Franz et al., 1996). Interestingly, Nos1^CreER;Ai9 mice, in which cells expressing Cre driven by the NOS I promoter co-express the gene for the fluorescent reporter tdTomato, show labeling specifically in type I SGN fibers and their terminals beneath IHCs when induced at (P)10. However, labeling was not seen in hair cells or efferent fibers (Vyas et al., 2019). Cre lines can often under-report the true expression pattern of a gene (Schmidt et al., 2013) so the lack of expression of Cre in some cells in the Nos1^CreER;Ai9 mouse line does not necessarily imply a true lack of expression of NOS I. Indeed, functional experiments using a non-specific NOS inhibitor support NOS activity in IHCs. Live imaging using the NO-specific dye DAF-2, along with calcium indicator dyes, showed that externally-applied ATP increases the intensity of both calcium and NO dependent fluorescence in mature guinea pig IHCs (Shen et al., 2003). Further work using similar techniques showed that NO is activated by, and then inhibits, calcium influx via a cGMP-dependent protein kinase feedback loop in mature IHCs (Shen et al., 2005) with similar findings reported in adult OHCs (Shen et al., 2006).

Later experiments suggested that NO may be involved in retrograde facilitation at the immature IHC to MOC synapse. A mechanism first discovered in the brain, retrograde facilitation describes activation of pre-synaptic terminals by “on demand” neuromodulator release from their post-synaptic targets, leading to enhanced synaptic transmission (Regehr et al., 2009). In whole-cell patch-clamp experiments from developing IHCs with transient MOC innervation, retrograde facilitation generated increased quantum content of neurotransmitter release from pre-synaptic MOC efferent terminals. This quantum content increase could be mimicked by the application of NO donors and reduced by extracellular NO scavengers. The facilitation was also enhanced by manipulations to the calcium concentration within IHCs, suggesting calcium-dependent synthesis and release of NO from IHCs (Kong et al., 2013). The efferent innervation of developing IHCs by MOC neurons has been implicated in development of ascending auditory pathways (Clause et al., 2014), including refinement of MNTB axons that in turn inhibit MOC somata in the brainstem (Torres Cadenas et al., 2020). Therefore, facilitation of MOC efferent inhibition of IHCs by NO likely has roles in development of both ascending and descending cochlear circuitry.

Neuropeptides

There are over 100 known neuropeptides serving diverse purposes throughout the central and peripheral nervous system (Russo, 2017). Several of these have been identified in the cochlear perivasculature and in sympathetic fibers in the modiolus (Eybalin, 1993). As these studies deal with the regulation of cochlear blood flow rather than neurotransmission, they are not reviewed here. Below, we instead focus on studies reporting neuropeptide neurotransmission within the cochlea and possible functions of this signaling.

Calcitonin-gene related peptide (CGRP)

Calcitonin-gene related peptide (CGRP) is a potent vasodilator and activator of sensory pain fibers (Russell et al., 2014). CGRP has long been suspected to be a modulator of neuronal activity in the mammalian cochlea. There are two nearly identical isoforms of CGRP: αCGRP, which was originally discovered in the rat thyroid and is produced through alternative splicing of the calcitonin gene (Rosenfeld et al., 1983), and βCGRP, which differs by a single amino acid residue as the alternatively-spliced product of a closely-related gene (Amara et al., 1985). Isoform specific localization of CGRP is rarely specified in inner ear literature; thus all following references to CGRP are α/β non-specific unless otherwise indicated. CGRP has been localized to the inner spiral bundle (ISB), tunnel crossing fibers, and below OHCs in various species (Eybalin, 1993), including guinea pig (Cabanillas and Luebke, 2002; Qi et al., 2004), rat (Vetter et al., 1991), mouse (Maison et al., 2003b, 2003a; Nitecka and Sobkowicz, 1996; Wu et al., 2018), hamster (Simmons et al., 1996b) and human (Kong et al., 2002; Schrott-Fischer et al., 2007). EM studies show immunostaining for CGRP in the LOC fiber varicosities contacting type I SGNs, and in the MOC terminals under OHCs in multiple species (reviewed in Eybalin, 1993). Interestingly, this labeling has not been found in humans (Kong et al., 2002; Schrott-Fischer et al., 2007). CGRP expression in the MOC fibers of hamsters is present only in the apex, while there is no tonotopy to the expression in LOCs (Simmons et al., 1996a). In a CGRP-EYFP knock-in mouse line, there is a tonotopic gradient of EYFP fluorescence in type II SGN dendrites of young adult mice (Wu et al., 2018). However, as genetic reporter expression does not always faithfully reproduce endogenous expression of a gene of interest (Schmidt et al., 2013), complementary experiments are needed to unequivocally conclude the presence of the peptide in type II SGNs. CGRP reactivity has been found in supporting cells of the human (Kong et al., 2002) and guinea pig (Qi et al., 2004) as well as in the guinea pig stria vascularis and osseous spiral lamina (Qi et al., 2004).

In vivo evidence for CGRP as a cochlear neuromodulator comes from experiments with αCGRP knockout mice. These mice, which also lack βCGRP, have normal ABR and DPOAE thresholds but decreased suprathreshold wave 1 ABR amplitudes. These results suggest normal cochlear mechanics and OHC function, but impaired transmission at the IHC-type I SGN synapse (Maison et al., 2003b). Given the location of the impairment and the demonstrated presence of CGRP in the LOC efferent system, it is possible that CGRP released from LOC efferent neurons exerts a selective, post-synaptic effect on type I SGNs (Maison et al., 2003b; Safieddine et al., 1997). However, the mechanism of synaptic dysfunction in the type I SGNs of αCGRP knockout mice is unknown. Defining a role for CGRP in the organ of Corti distinct from its roles in supporting cells, stria vascularis, and vasculature requires further investigation.

Substance P

Early work found conflicting evidence of the presence of substance P in the various components of the lower auditory system. Substance P was reported in the cochlea based on radioimmunoassay (Nowak et al., 1990). However, different findings on localization were reported both within and across species. In some guinea pig studies, no evidence was found of immunolabeling for substance P in the organ of Corti, spiral ganglion, auditory nerve, or cochlear nucleus (Davies, 1982). Yet in other guinea pig studies, findings included immunostaining of cochlear hair cells and weak immunostaining in the SG (Nowak et al., 1986), immunoreactivity in OHC and IHC areas (Schickinger et al., 1996), and immunoreactivity in neural elements beneath IHCs with occasional SG somatic labeling (Ylikoski et al., 1989). In rabbit, ~50% of basal spiral ganglion cells were found to show substance P-like immunoreactivity, but no immunoreactivity was seen in the organ of Corti (Ylikoski et al., 1984). In human, substance P was found in all SG cells (Anniko et al., 1995).

Despite a lack of clarity on substance P localization in the cochlea, the substance P receptor, NK1 has been localized to SGNs (Sun et al., 2004), and several studies support a functional role of substance P in the cochlea. Intracochlear perfusion of the NK1 receptor agonist substance P methyl ester (SPME) caused a dose-dependent increase in the amplitude of the CAP and the negative summating potential. These effects could be blocked by the application of an antagonist of substance P and suggest a function for substance P in modulating the auditory nerve directly (Nario et al., 1995). Application of substance P to dissociated type I SGNs has multiple effects; one group has shown prolonged duration and increased latency of APs, and suppression of calcium and voltage-gated potassium currents (Sun et al., 2004). Another has shown intracellular calcium release through the G-protein coupled phospholipase-C (PLC) pathway, and activation of a non-selective cation current which depolarizes SGNs (Ito et al., 2002). Depolarization of SGNs increases excitability, and indeed, extracellular potentials recorded in vivo from the subsynaptic region of IHCs show an increase in firing rate upon substance P iontophoresis, an effect that can be blocked by the specific substance P antagonist, spantide (Schickinger et al., 1996).

In contrast to the excitation of SGNs, application of substance P to isolated guinea pig OHCs decreases a non-selective cation conductance leading to inhibition. This effect is likely mediated by a PTX-insensitive G-protein pathway (Kakehata et al., 1995, 1993), but it is not clear through which receptor this pathway is activated (Kakehata et al., 1995). Whole-cell patch-clamp recordings suggest that intracellular calcium is not necessary for this response (Kakehata et al., 1995) and this is supported by the finding that substance P fails to elicit a change in intracellular calcium levels when applied to isolated guinea pig OHCs (Ikeda et al., 1991). A decrease in a non-selective cation conductance leads to hyperpolarization of the OHCs, therefore these results suggest that substance P activity could be a means to regulate OHC electromotility.

While substance P clearly has effects on cochlear physiology through action on both SGNs and OHCs, its site of release and full range of potential actions are still unknown and warrant further investigation.

Neuropeptide Y

Though neuropeptide Y (NPY) is most often associated with regulation of blood flow in the peripheral nervous system, NPY signaling is additionally implicated in neuropsychiatric, neurologic, and homeostatic properties in the central nervous system, suggesting a direct neuromodulatory role. (Alviña et al., 2021). In the rate organ of Corti, (NPY) immunoreactivity has been found in IHCs, OHCs, pillar cells, Deiters cells, and type I and II SGNs (Gomide et al., 2009). It has also been found in a subpopulation of SGN somata (but not fibers) in humans (Anniko et al., 1995). These localization patterns suggest that cochlear NPY may also have a neuromodulatory function, rather than exclusively controlling cochlear blood flow (Eybalin, 1993). Functionally, moderate noise exposure has been reported to increase NPY expression in SGNs (Gomide et al., 2009). Given the roles of NPY in the central nervous system, perhaps cochlear release of NPY plays a role in the responses to changing cochlear energy levels or to sound-evoked trauma.

Opioid Peptides

Initial histological studies in the cochlea demonstrated markers of opioid peptides, including Met-enkephalin, with biochemical evidence for increased production following noise exposure (Eybalin, 1993). Immuno-colocalization of opioid receptors and ChAT suggested that opioid receptors are present on auditory and vestibular efferents (Eybalin et al., 1988). Later work also found opioid receptors under both IHCs and OHCs in the guinea pig and mouse cochleae (Jongkamonwiwat et al., 2006; Nguyen et al., 2014) and in the spiral ganglion of the mouse and human (Nguyen et al., 2014).

Systemic administration of opioid painkillers in rodents increases the amplitude of peak 1 in ABR recordings, while perfusion into the middle ear increases the CAP N1-P1 amplitude, indicating increased sound-evoked responses in the auditory nerve. DPOAEs were normal, suggesting that clinical opioid agonists act at the IHC-type I SGN synapse and not at OHCs (Ramírez et al., 2020). Clinically, opioid-associated hearing loss is a common comorbidity in patients with opioid use disorder, and there is one published case of a temporary (but reproducible) hearing loss after oxymorphone inhalation (MacDonald et al., 2015).

The precise mechanisms of opioid action in the cochlea are under active investigation. Opioid peptide activation of the LOC system is well reviewed elsewhere (Wersinger and Fuchs, 2011). However, activation of the α9α10 nAChR by opioid agonists makes it difficult to pharmacologically isolate opioid effects in LOC neurons (Lioudyno et al., 2002). As for individual peptides, there is some in vivo evidence that dynorphin and dynorphin-like drugs might work as inhibitory neuromodulators at the LOC-type I SGN synapse (Le Prell et al., 2014), though this result conflicts with the CAP trends mentioned above. Recently, a pathway was proposed by which dynorphins facilitate glutamate-NMDA receptor interactions, ultimately contributing to glutamate excitotoxity after prolonged noise exposure (Sahley et al., 2019, 2013).

Protons

In addition to critical roles in regulating pH, protons have been established as intercellular signaling molecules. The vacuolar ATPase on synaptic vesicles produces the pH and electrical gradients required to load neurotransmitters through vesicular transporters, yielding acidic vesicles that release protons along with neurotransmitter. Therefore, vesicular release of glutamate, GABA, glycine, acetylcholine, and monoamines also results in proton release (Figure 1–4) (reviewed in Hnasko and Edwards, 2012). Extracellular protons are implicated in both pre- and post-synaptic actions. Protons can inhibit pre-synaptic voltage-gated ion channels to negatively regulate subsequent neurotransmitter release. This is especially apparent at highly active synapses that release many vesicles, and thus many protons, such as ribbon synapses in retinal bipolar cells (Palmer et al., 2003), vestibular hair cells (Almanza et al., 2008), and also likely cochlear IHCs. Similarly, in post-hearing gerbil and rat IHCs a transient proton-mediated block of pre-synaptic calcium currents occurs upon multivesicular release, reducing pre-synaptic neurotransmitter release (Vincent et al., 2018).

Protons also have post-synaptic functions at receptors for other neurotransmitters, as well as at proton-specific receptors. Indeed, protons released from neurotransmitter-containing vesicles are implicated in post-synaptic function in the cochlea (Soto et al., 2018). Some neurotransmitter receptors including NMDA and kainate-type glutamate receptors are inhibited by protons, while GABA A receptors have variable responses to fluctuations in pH (reviewed in Soto et al., 2018). There are numerous extracellular proton sensing molecules such as the widely-expressed acid sensing ionic channels (ASIC) which are trimeric, cation permeable, voltage-insensitive channels (reviewed in Soto et al., 2018). All four ASIC family genes encoding six channel subunits have been localized to SGNs. ASIC channels mediate proton-evoked, occasionally supra-threshold excitation and inward currents in SGNs (González-Garrido et al., 2015; Peng et al., 2004a) and vestibular afferents (Mercado et al., 2006). ASIC2 KO mice have an increased resistance to temporary, but not permanent, ABR threshold shifts after acoustic exposure, suggesting a role for protons in noise-evoked trauma (Peng et al., 2004a). ASIC3 KO animals have early age-related hearing deficits (Hildebrand et al., 2004). Thus, protons can act as traditional neurotransmitters utilizing vesicular release with activity at post-synaptic receptors, in addition to their diverse modulatory effects at both pre- and post-synaptic sites.

Neurotransmitter co-release

The above sections detail neurotransmitters described in the cochlea; however, over 200 molecules can function as neurotransmitters in the nervous system (Svensson et al., 2018) and more cochlear signaling molecules and mechanisms are likely yet to be described. In the brain, many cells utilize co-release of neurotransmitters, which is well reviewed in the CNS and PNS (Burnstock, 2004; Hnasko and Edwards, 2012; Svensson et al., 2018; Tritsch et al., 2016 and others). Dale’s Principle (which was coined by Eccles in reference to Henry Dale’s work (Eccles et al., 1954; Svensson et al., 2018; Tritsch et al., 2016)) is generally interpreted to mean that a neuron releases a single neurotransmitter. However, numerous examples of neurotransmitter co-release have altered this view. Complex mechanisms of neurotransmitter co-release include release of multiple neurotransmitters from a cell, release from the same or different axon terminals, developmentally transient co-release, non-vesicular release of diffusible compounds, dendritic release, differential modulation by activity, and pre- and post-synaptic functions of released molecules (Hnasko and Edwards, 2012; Svensson et al., 2018). Many cochlear cells likely co-release neurotransmitters, perhaps utilizing these complex mechanisms of intercellular communication.

Co-localization of markers for neurotransmitter synthesis, vesicular loading, or uptake are used to infer co-release, but functional studies are necessary for confirmation. In particular, the efferent system is likely to demonstrate complex co-release of neurotransmitters. It has a well-characterized cholinergic function (Fuchs and Lauer, 2019), yet both LOC and MOC neurons immunolabel for markers of GABA or its synthesizing enzyme GAD. MOC neurons also show co-localization for CGRP (Fex and Altschuler, 1986; Maison et al., 2006, 2003a; Wedemeyer et al., 2013). Functional release of GABA from MOC terminals has been demonstrated (Wedemeyer et al., 2013). It is still unclear whether GABA and ACh are released from the same MOC axon terminals, and whether they are co-released in response to the same stimuli in vivo.

In addition to ACh and GABA, LOC neurons express markers for several other neurotransmitters including dopamine and peptides such as enkephalins and CGRP. Peptide release from efferent terminals is likely modulated by activity on different timescales than for classic small molecule neurotransmitters because peptides are synthesized in the soma, then transported to the axon terminal in dense core vesicles instead of being synthesized in axon terminals (Boarder, 1989; Hnasko and Edwards, 2012).

Additional examples of cochlear neurotransmitter co-release are described in above sections, including demonstrated NO (Kong et al., 2013) and proton (Soto et al., 2018) release from glutamatergic IHCs. Further study will likely demonstrate additional complexity of intercellular signaling involving co-release in the cochlea.

Conclusion

Studies utilizing histology, biochemistry, pharmacology, neurophysiology, auditory function tests, and cell biology have described numerous neurotransmitters with potential functions in the cochlea, and more substances are likely to be described as the list of loosely defined neurotransmitters in the nervous system grows. Powerful new tools involving genetic isolation and manipulation of cells or synapses will add to our specific knowledge of the function of each neurotransmitter. However, it is becoming clear that neurotransmitters likely do not operate in the cochlea in isolation, and that hearing involves complex and dynamic cellular interplay both within the cochlea and bi-directionally with the brain.

Highlights.

Multiple neurotransmitters have been identified in the cochlea, each with diverse mechanisms of release and complex patterns of post-synaptic receptors
Recent studies demonstrate the functions of a broad array of neurotransmitters that have been hypothesized to exist in the cochlea
Cochlear neurotransmitter signaling is likely dynamic in order to encode both the precision and the complexity of acoustic stimuli

Acknowledgements:

This work supported by the Intramural Research Program of the NIH, NIDCD, Z01 DC000091 (CJCW).

Footnotes

Conflicts of Interest: The authors declare no competing financial interests

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PERMALINK

Diverse identities and sites of action of cochlear neurotransmitters

Siân R Kitcher

Alia M Pederson

Catherine JC Weisz

Abstract

Introduction

Glutamate

Glutamate release from IHCs

Figure 1:

Glutamate release from OHCs

Acetylcholine

Figure 2.

Cholinergic signaling from MOC neurons onto developing IHCs

Cholinergic signaling from MOC neurons onto OHCs

Cholinergic reinnervation of IHCs in aging

Cholinergic signaling from LOC neurons

GABA

Figure 3.

Glycine

Purines

Catecholamines

Dopamine

Figure 4.

Noradrenaline / adrenaline

Serotonin

Nitric Oxide

Neuropeptides

Calcitonin-gene related peptide (CGRP)

Substance P

Neuropeptide Y

Opioid Peptides

Protons

Neurotransmitter co-release

Conclusion

Highlights.

Acknowledgements:

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

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