CNTN2 Deficiency Disrupts Ascending Auditory Neuroglial Interactions and Redox Homeostasis in Neural Presbycusis

Neural presbycusis disrupts auditory timing and speech perception, yet its molecular basis remains poorly understood. This study identifies Cntn2 as the Ranvier's nodal molecule significantly downregulated in aged auditory nerves. Cntn2 heterozygous knockout (Cntn2^+/-) mice showed elevated auditory brainstem response thresholds and prolonged wave latencies and interpeak intervals, whereas distortion product otoacoustic emission thresholds were largely preserved. Hair cell and ribbon synapses were preserved, with no obvious ultrastructural changes, suggesting that overt hair cell loss or synaptic structural loss is unlikely to be the main cause of the early phenotype. Instead, transmission electron microscopy revealed myelin outfoldings and aberrant node of Ranvier morphology in myelinated auditory nerve fibers, accompanied by increased Schwann cell density. Multiplex immunofluorescence and Western blot analysis showed disruption of nodal molecular organization along the ascending auditory pathway from cochlea to auditory cortex. Transcriptomic profiling and oxidative stress assays further linked CNTN2 deficiency to altered neuroglial interaction and redox imbalance. Early unilateral AAV-mediated CNTN2 restoration partially improved threshold and latency abnormalities. These findings identify CNTN2-dependent neuroglial integrity as an important contributor to auditory conduction of neural presbycusis and may provide a new direction for future therapeutic studies.