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Peer-reviewedCC BY 4.0Advanced Science

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

  • Penghui Chen1,2
  • Jingyi Zhu1,3
  • Sihan Huang1,3
  • Beibei Xu1,3
  • Maoli Duan1,4,5
  • Jingrong Lv1,3
  • Jiarui Chen2
  • Jun Yang1,3
  • Shule Hou1,3
5 affiliations
  1. 1Department of Otorhinolaryngology‐Head and Neck Surgery Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
  2. 2Department of Otorhinolaryngology‐Head and Neck Surgery Shanghai Children's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
  3. 3Ear Institute Shanghai Jiao Tong University School of Medicine Shanghai China
  4. 4Ear Nose and Throat Patient Area, Trauma and Reparative Medicine Theme Karolinska University Hospital Stockholm Sweden
  5. 5Division of Ear, Nose and Throat Diseases Department of Clinical Science, Intervention and Technology Karolinska Institutet Stockholm Sweden
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{chen2026cntn2,
  title = {{CNTN2 Deficiency Disrupts Ascending Auditory Neuroglial Interactions and Redox Homeostasis in Neural Presbycusis}},
  author = {Penghui Chen and Jingyi Zhu and Sihan Huang and Beibei Xu and Maoli Duan and Jingrong Lv and Jiarui Chen and Jun Yang and Shule Hou},
  journal = {Advanced Science},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.202522800},
  url = {https://doi.org/10.1002/advs.202522800},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - CNTN2 Deficiency Disrupts Ascending Auditory Neuroglial Interactions and Redox Homeostasis in Neural Presbycusis
AU  - Penghui Chen
AU  - Jingyi Zhu
AU  - Sihan Huang
AU  - Beibei Xu
AU  - Maoli Duan
AU  - Jingrong Lv
AU  - Jiarui Chen
AU  - Jun Yang
AU  - Shule Hou
PY  - 2026
DA  - 2026/10/26
JO  - Advanced Science
DO  - 10.1002/advs.202522800
UR  - https://doi.org/10.1002/advs.202522800
AB  - 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.
SN  - 2198-3844
ER  -