Impaired postsynaptic function and disruption of intermediate filaments in GLAST-knockout-induced hidden hearing loss

Hidden hearing loss (HHL) is an inner ear disorder that is characterized by synaptopathy despite normal hearing thresholds. In HHL mouse models, synaptopathy and decreased wave I amplitude were the key pathological and auditory features. However, the underlying molecular mechanisms of HHL remain unclear. We used gene-knockout mice to investigate the potential mechanisms underlying synaptopathy. The mice displayed pathological and auditory features consistent with HHL following glutamate-aspartate transporter [GLAST; also known as solute carrier family 1 member 3 (SLC1A3), or excitatory amino acid transporter 1] knockout (KO). In KO mice, surface expression of postsynaptic proteins was significantly decreased in the inner ear, and the cytoskeleton, especially intermediate filaments, was impaired. We also observed susceptibility to overt hearing loss in response to aging. Our findings indicate that GLAST KO induces synaptopathy, disrupts intermediate filament organization, and accelerates age-related hearing loss, providing insights into HHL development and its progression to overt hearing loss.