Noise can damage the auditory system leading to hearing loss. High-intense noise can cause irreversible degeneration of spiral ganglion neurons (SGN) and hair cells leading to permanent threshold shift (PTS) in hearing. Noise also can induce temporal threshold shift (TTS) and hidden hearing loss (HHL), which appears normal hearing threshold and has no apparent hair cell loss, but has extensive loss of synaptic connections (ribbon synapses) between inner hair cells (IHCs) and auditory nerves (ANs) with a delayed degeneration of SGNs and their central projections (Boero et al., 2018; Kobel et al., 2017; Kujawa and Liberman, 2009, 2015; Lin et al., 2011). It is estimated that more than 100 million people have noise-induced hearing loss (NIHL), which accounts for ∼10 % of patients in the otolaryngology clinics (Hind et al., 2011; Kumar et al., 2012). However, except physical protections such as using earplugs, there are no pharmacological drugs or treatments currently available in the clinic for treatment of cochlear synaptopathy and NIHL.

In previous studies, many drugs, antagonists and agonists of different cell signaling pathways, such as neurotrophins, TrkB agonists, and glucocorticoids, were tested for prophylactic and therapeutic interventions against NIHL (Fernandez et al., 2021; Han et al., 2015; Harrop-Jones et al., 2016; Ingersoll et al., 2020; Poduslo and Curran, 1996). Since loud noise can stimulate the production of reactive oxygen species, targeting the free-radical pathways was also tested and showed some promises (He et al., 2021). However, none of these compounds has been approved against NIHL in the clinic. Moreover, most of previous studies administrated drugs in pre-exposure (preventive) manners; only a few studies did post-exposure administration to test the therapeutic effect against NIHL or cochlear synaptopathy (Bao et al., 2013; Dhukhwa et al., 2019; Fernandez et al., 2021; Ingersoll et al., 2020; Seist et al., 2020; Shen et al., 2007; Yu et al., 2018). In addition, since the existence of blockade of crossing the blood-labyrinth barrier (BLB), some drugs were shown to have effects in the local administration (e.g., via the posterior semicircular canal) but not in the systemic administration (Fernandez et al., 2021; Poduslo and Curran, 1996). Thus, the efficiency of treatment is also challenged by the delivery method. Finally, most of previous studies mainly focused on noise-induced hair cell and SGN loss; only a few studies investigated noise-induced cochlear synapse degeneration (Fernandez et al., 2021; Hu et al., 2020; Ingersoll et al., 2020; Rouse et al., 2020; Seist et al., 2020; Yu et al., 2018). Thus, the underlying mechanism for noise-induced cochlear synaptopathy still remains largely unclear.

Loud noise can stimulate hair cells and neurons over-activation, which can increase K+ efflux to elevate extracellular K+ concentration leading to K+-excitotoxicity (Konishi and Salt, 1980; Melichar et al., 1980; Salt and Konishi, 1979). It is well-known that K+-excitotoxicity produced by high extracellular K+ concentration can cause synapse and neuron degeneration in the brain (Deshpande et al., 2007; Kawasaki et al., 1988; Walsh et al., 2014). Our previous study also demonstrated that high extracellular K+ concentration in in vitro preparation could cause cochlear ribbon synapse degeneration, which could be attenuated by K+ channel blockers (Zhao et al., 2021). In this study, we found that systemic administration of K+ channel blockers in mice in vivo before or after noise exposure significantly ameliorated cochlear synapse degeneration and NIHL. Our findings open a new avenue for treating cochlear synaptopathy and NIHL. This study also demonstrates that K+-excitotoxicity plays a critical role in the cochlear synapse degeneration and NIHL.