Extracellular signal-regulated kinases 1/2 (ERK1/2) is a key regulator of noise-induced hidden hearing loss.

Currently, the accepted mechanism of noise-induced hidden hearing loss (NIHHL) is cochlear synaptopathy which disrupts afferent synapses of the cochlear inner hair cells; however, the molecular basis underlying the cochlear synaptopathy remains unclear. In this study, adult mice were subjected to single or twice moderate noise exposure (the 1st , and 2nd NE, respectively) . The results showed that mice after the 1st NE exhibited a temporary threshold shift (TTS) that recovered within two weeks, while immunofluorescence staining revealed loss of ribbon synapses. After 2nd NE, by contrast, permanent threshold shifts were observed, with more severe loss of ribbon synapses. Furthermore, we found that ERK1/2 was phosphorylated (p-ERK1/2) in the cochlea following both the 1st and 2nd NE, and the peak of p-ERK1/2 emerged earlier after the 2nd NE. Administration of the ERK1/2 inhibitor SCH772984 significantly restored hearing compared with controls. Taken together, our findings demonstrate that noise exposure activates ERK1/2 phosphorylation in the cochlea, leading to hearing loss, and indicate that activation of the ERK1/2 pathway may represent a cellular mechanism underlying NIHHL.