Physiopathological Relevance of D-Serine in the Mammalian Cochlea

Jing Wang,Jérôme Ruel,Jonathan V Sweedler,Nicolas Serratrice,Jean-Pierre Mothet,Jean-Luc Puel,Cindy J Lee,Florence François

doi:10.3389/fncel.2021.733004

Abstract

NMDA receptors (NMDARs) populate the complex between inner hair cell (IHC) and spiral ganglion neurons (SGNs) in the developing and mature cochlea. However, in the mature cochlea, activation of NMDARs is thought to mainly occur under pathological conditions such as excitotoxicity. Ototoxic drugs such as aspirin enable cochlear arachidonic-acid-sensitive NMDAR responses, and induced chronic tinnitus was blocked by local application of NMDAR antagonists into the cochlear fluids. We largely ignore if other modulators are also engaged. In the brain, D-serine is the primary physiological co-agonist of synaptic NMDARs. Whether D-serine plays a role in the cochlea had remained unexplored. We now reveal the presence of D-serine and its metabolic enzymes prior to, and at hearing onset, in the sensory and non-neuronal cells of the cochlea of several vertebrate species. In vivo intracochlear perfusion of D-serine in guinea pigs reduces sound-evoked activity of auditory nerve fibers without affecting the receptor potentials, suggesting that D-serine acts specifically on the postsynaptic auditory neurons without altering the functional state of IHC or of the stria vascularis. Indeed, we demonstrate in vitro that agonist-induced activation of NMDARs produces robust calcium responses in rat SGN somata only in the presence of D-serine, but not of glycine. Surprisingly, genetic deletion in mice of serine racemase (SR), the enzyme that catalyzes D-serine, does not affect hearing function, but offers protection against noise-induced permanent hearing loss as measured 3 months after exposure. However, the mechanisms of activation of NMDA receptors in newborn rats may be different from those in adult guinea pigs. Taken together, these results demonstrate for the first time that the neuro-messenger D-serine has a pivotal role in the cochlea by promoting the activation of silent cochlear NMDAR in pathological situations. Thus, D-serine and its signaling pathway may represent a new druggable target for treating sensorineural hearing disorders (i.e., hearing loss, tinnitus).

Highlights

N-methyl D-aspartate receptors (NMDARs) are major excitatory ligand-gated ion channels in the central nervous system (CNS), and are critical mediators for synaptic plasticity, learning, and memory
L-glutamate (89.00 ± 14 pmol/μg protein; n = 7) was by far the most abundant amino acid in the mouse cochlea. These results demonstrated that D-serine is present in the adult mouse cochlea at a relatively low level compared to L-serine, glycine, or glutamate (Figure 2C)
Because aberrant NMDA receptors (NMDARs) activation has been consistently found to contribute to trauma-induced cochlear damage (Guitton et al, 2003; Ruel et al, 2008; Bing et al, 2015; Sanchez et al, 2015), we examined the role of D-serine in noise-induced hearing loss (NIHL)

Summary

Introduction

N-methyl D-aspartate receptors (NMDARs) are major excitatory ligand-gated ion channels in the central nervous system (CNS), and are critical mediators for synaptic plasticity, learning, and memory. Glycine was first proposed to serve as the coagonist of NMDARs (Johnson and Ascher, 1987; Forsythe et al, 1988; Kleckner and Dingledine, 1988) further evidence indicated that at many central excitatory synapses within different brain areas, the amino acid D-serine is the primary endogenous co-agonist of NMDARs (Mothet et al, 2000). Both D-serine and glycine can support NMDAR-dependent long-term changes in synaptic plasticity and cognitive processes (Li et al, 2013; Le Bail et al, 2015; Neame et al, 2019). NMDARs are not functional at mature IHC-SGN synapses (Ruel et al, 1999; Glowatzki and Fuchs, 2002), despite the suggestions that they regulate surface expression of AMPARs (Chen et al, 2007; Sanchez et al, 2015), and that they participate in glutamatergic synaptic transmission in the developing cochlea by promoting spontaneous activity and survival of SGNs (Zhang-Hooks et al, 2016)

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