MODULATION OF D-SERINE/NMDAR SIGNALING AS A THERAPEUTIC AVENUE FOR EXCITOTOXIC AUDITORY SYNAPTOPATHY

Introduction: Excessive glutamate release at the inner hair cell(IHC)–spiral ganglion neuron (SGN)synapse, triggered by noise, ototoxins, or aging, drives AMPAR-mediated excitotoxic synaptopathy. This pathology, marked by terminal swelling, ribbon synapse loss, and reduced auditory nerve output despite normal thresholds, underlies noise-induced “hidden hearing loss.” In contrast, cochlear NMDARs remain largely silent under physiological conditions but can be engaged under pathological stress. Since D-serine, synthesized by serine racemase(SR)in cochlear cells, acts as an NMDAR co-agonist, its modulation may rebalance NMDAR and AMPAR activity during excitotoxic insult.
Methods: We examined the role of D-serine–induced NMDAR activation in cochlear synaptopathy and repair using two models:(i)a kainate-induced synaptopathy model in neonatal (P3) mouse cochlear explants, and (ii) an impulse noise exposure model (146 dB SPL, 1 pulse/s, 700s) in vivo. Molecular assays, ultrastructural analysis, auditory brainstem response(ABR)recordings, and acoustic startle reflex tests were combined to assess D-serine’s contribution to NMDAR function and excitotoxic pathophysiology.
Results: We examined the role of D-serine–induced NMDAR activation in cochlear synaptopathy and repair using two models:(i)a kainate-induced synaptopathy model in neonatal (P3) mouse cochlear explants, and (ii)an impulse noise exposure model (146dB SPL, 1pulse/s, 700s) in vivo. Molecular assays, ultrastructural analysis, auditory brainstem response(ABR)recordings, and acoustic startle reflex tests were combined to assess D-serine’s contribution to NMDAR function and excitotoxic pathophysiology.
Conclusion: These findings identify D-serine–mediated activation of silent cochlear NMDARs as a protective mechanism against AMPAR-driven excitotoxic synaptopathy. Targeting D-serine signaling may therefore represent a promising therapeutic strategy for auditory disorders associated with excitotoxic damage.