Blocking axon-glial mechanotransduction to prevent concussive brain injury.

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.