Noise-induced hearing loss (NIHL) poses an emerging global health problem with only ear protection or sound avoidance as preventive strategies. The cochlea receives some protection from medial olivocochlear efferent neurons, providing a potential target for therapeutic enhancement. Cholinergic efferents release acetylcholine (ACh) to hyperpolarize and shunt the outer hair cells (OHCs), reducing sound-evoked activation. The (α9)2(α10)3 nicotinic ACh receptor (nAChR) on the OHCs mediates this effect. Transgenic knockin mice with a gain-of-function nAChR (α9L9'T) suffer less NIHL. α9 knockout mice are more vulnerable to NIHL but can be rescued by viral transduction of the α9L9'T subunit. In this study, an HA-tagged gain-of-function α9 isoform was expressed in wild-type mice to reduce NIHL. Synaptic integration of the virally expressed nAChR subunit was confirmed by HA immunopuncta localized to the postsynaptic membrane of OHCs. After noise exposure, AAV2.7m8-CAG-α9L9'T-HA (α9L9'T-HA)-injected mice had less hearing loss (auditory brainstem response [ABR] thresholds and threshold shifts) than did control mice. ABRs of α9L9'T-HA-injected mice also had larger wave-1 amplitudes and better recovery of wave-1 amplitudes post noise exposure. Thus, virally expressed α9L9'T combines effectively with native α9 and α10 subunits to mitigate NIHL in wild-type cochleas.
© 2025 The Authors.

The preservation of synaptic integrity and physiological activity is pivotal for post-traumatic auditory rehabilitation following acoustic overexposure. Neuritin, a neurotrophic factor that facilitates synapse formation, maturation, and enhanced synaptic transmission, is essential for synapse development. In this study, we established a noise-induced cochlear synaptopathy model in CBA/CaJ mice, revealing a temporal association between endogenous Neuritin expression and synaptic density. Furthermore, administration of recombinant Human Neuritin (rhNeuritin) effectively preserves synaptic density in the cochlear basal turn at 7 days and 14 days following noise exposure. Importantly, it preserves the density of functional synapses (represented by overlapping CtBP2 and GluA2 puncta) and synapse function (indicated by ABR I wave amplitudes), thus diminishing the impairment of auditory function. In addition, rhNeuritin reverses the decrease in phosphorylated extracellular signal-regulated protein kinase 1/2 (p-ERK1/2) levels resulting from noise exposure. By primarily preserving both the number and functionality of synapses in the basal turn, potentially via the induction of ERK1/2 phosphorylation, rhNeuritin mitigated hearing loss. These findings underscore the protective efficacy of rhNeuritin against noise-induced synaptic injury.
© 2025 The Authors.

A/J mice exhibited a severe hearing loss (HL) at juvenile stage. Up-to-date, studies on HL in A/J mice have mostly focused on the damage or dysfunction of hair cells (HCs), spiral ganglion neurons (SGNs), and stereocilia. We examined A/J mice at the early postnatal stage and found that the damage and the loss of outer hair cells (OHCs) are not severe enough to explain the profound HL observed at this age, which suggests that other cochlear defects may be responsible for HL. To better understand the mechanisms of early-onset HLin A/J mice, we characterized the pathology of the cochlea from postnatal day 3 to day 21.
Our results showed defects in cochlear HC stereocilia and MET channel function as early as 3 days old. We also found abnormal localization and a significant reduction in the number of ribbon synapses in 2-week-old A/J mice. There are also abnormalities in the cochlear nerve innervation and terminal swellings in 3-week-old A/J mice.
All of the abnormalities of cochlear existed in the A/J mice were identified in the juvenile stage and occurred before HCs or auditory nerve loss and was the initial pathological change. Our results suggest that developmental defects and subsequent cochlear degeneration are responsible for early-onset hearing loss in A/J mice.
© 2024 American Association for Anatomy.

During development, microglia prune excess synapses to refine neuronal circuits. In neurodegeneration, understanding the role of microglia-mediated synaptic pruning in circuit remodeling and dysfunction is important for developing therapies aimed at modulating microglial function. Here, we analyzed microglia-mediated synapse disassembly of degenerating postsynaptic neurons in the inner retina. After inducing transient intraocular pressure elevation to injure retinal ganglion cells, microglia increase in number, shift to hyper-ramified morphology, and exhibit greater process movement. Furthermore, due to the greater number of microglia, there is increased colocalization of microglia with synaptic components throughout the inner plexiform layer and with excitatory synaptic sites along individual ganglion cell dendrites. Microglia depletion partially protects ganglion cell function, suggesting that microglia activation may be neurotoxic in early neurodegeneration. Our results demonstrate the important role of microglia in synapse disassembly in degenerating circuits, highlighting that microgliosis is the primary mechanism for increased synapse colocalization early after neuronal injury.
© 2025 The Author(s).

This study examined the effect of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), an anion channel blocker of voltage-dependent anion channel 1 (VDAC1), on noise-induced hearing loss (NIHL) and its underlying mechanisms.
Cochlear explants and House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were used to assess the effect of DIDS in vitro. Auditory brainstem responses were used to assess auditory functions in mice. Immunofluorescence staining of myosin 7a and CTBP2 were used to examine hair cells and synaptic ribbons. The accumulation of reactive oxygen species (ROS) was measured by 4-HNE staining. The gene expression changes of cochlea were analyzed using RNA sequencing.
DIDS reduced the levels of ROS in cochlear explants and attenuated cell death caused by hydrogen peroxide in both cochlear explants and HEI-OC1 cells. In C57BL/6 mice, DIDS reduced ROS generation and tumor necrosis factor-α induced by noise exposure, thereby protecting outer hair cells and inner hair cell synaptic ribbons from noise-induced damage through a mechanism involving the PINK1/Parkin signaling pathway. The preventive effect of DIDS in cochlear explants was eliminated by mitophagy inhibition.
VDAC1 inhibition enhances mitophagy in cochlear hair cells, playing a critical role in defending against oxidative stress and inflammation. Downregulation of VDAC1 may thus be considered a therapeutic strategy for preventing cochlear hair cell damage and reducing NIHL.
© 2025 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.