BDNF Alleviates Noise-Induced Cochlear Synaptopathy Through Inhibition of Autophagy.

Brain-derived neurotrophic factor (BDNF) can protect against metabolic stress-induced synaptic damage via inhibiting autophagy in the brain. It was further proposed to prevent cochlear synaptopathy against the stress of noise exposure (NE). However, it remains elusive whether BDNF's protective role in cochlear synaptopathy is associated with the inhibition of autophagy in the cochlea. In this study, we found significantly increased expression of C-terminal-Binding Protein 2 (CtBP2) and Glutamate Receptor 2 (GluR2), accompanied by greatly reduced expression of microtubule-associated Protein 1 Light Chain 3 Beta (LC3B) and Lysosomal-Associated Membrane Protein 1 (Lamp1), suggesting that the application of BDNF into the cochlea can downregulate autophagy and play a protective role in ribbon synapses. Mechanistically, we simulated the inner ear exposed to NE using excitatory amino acid receptor agonists, N-methyl-D-aspartate(NMDA) and kainate (KA) treatment in cultured cochlear explant models and found that the changes of autophagic flux in the cochlea are mediated through phosphatidylinositol 3-kinase (PI3K), phosphorylated AKT (p-AKT)/AKT, and phosphorylated mTOR (p-mTOR)/mTOR signaling. BDNF enhances PI3K/AKT/mTOR signaling activity, correlating with reduced autophagosome formation and lysosomal degradation in cochlear explants. Therefore, our study indicates that BDNF suppresses autophagic flux to protect against noise-induced cochlear synaptopathy via activating PI3K/AKT/mTOR signaling, thereby suggesting a potential therapeutic strategy for noise-induced cochlear synaptopathy.