Blocking axon-glial mechanotransduction to prevent concussive brain injury

  • Acta Neuropathol Commun. 2025 Sep 29;13(1):205. doi: 10.1186/s40478-025-02117-6.
Chao Sun  1  2 ,  Di Ma  3  2 ,  Jacob Hansen  3  2 ,  Jeffrey R Tonniges  4 ,  Hongzhen Hu  5 ,  Liwen Zhang  6 ,  Chen Gu  7  8
Affiliations
  • 1. Molecular, Cellular and Developmental Biology graduate program, The Ohio State University, Columbus, OH, 43210, USA.
  • 2. Department of Biological Chemistry and Pharmacology, The Ohio State University, 182 Rightmire Hall, 1060 Carmack Road, OH, 43210, Columbus, USA.
  • 3. Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, 43210, USA.
  • 4. Campus Microscopy and Imaging Facility, The Ohio State University, Columbus, OH, 43210, USA.
  • 5. Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 6. Mass Spectrometry and Proteomics Facility, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
  • 7. Molecular, Cellular and Developmental Biology graduate program, The Ohio State University, Columbus, OH, 43210, USA. [email protected].
  • 8. Department of Biological Chemistry and Pharmacology, The Ohio State University, 182 Rightmire Hall, 1060 Carmack Road, OH, 43210, Columbus, USA. [email protected].
PMID: 41024271 DOI: 10.1186/s40478-025-02117-6
Abstract

All cells in the central nervous system (CNS) are considered mechanosensitive, but how they collectively respond to a concussive head impact and contribute to the transition from the primary to secondary injury remains unknown. Using a mouse model for mild traumatic brain injury (mTBI) or concussion, we report that blocking the activity of TRPV4 transient receptor potential channels inhibits mTBI-induced sequential changes of neurons and glial cells, as well as behavioral disturbances. A concussive head impact immediately induces axonal varicosities, preceding NMDA-receptor-mediated microglial activation and cortical demyelination. Afterward, these changes differentially and partially recover. Blocking TRPV4 channels before or after head impact markedly suppresses axon-glial and behavioral changes or enhances their recovery, respectively. Using knockout mice and AAV-Cre-mediated acute and cell-type-specific deletion, we further show that neuronal TRPV4 channels, as an mTBI target, regulate the homeostasis of axon mechanosensation and their hyperactivation causes axonal varicosity formation followed by axon-to-glia mechanotransduction.

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