Kavli Affiliate: Anna Molofsky and Jeanne Paz
| Authors: Nicholas M Mroz, Agnieszka Ciesielska, Nathan A Ewing-Crystal, Leah C Dorman, Rafael T Han, Jerika J Barron, Nicholas J Silva, Audrey Magsig, Anna V Molofsky, Ari B Molofsky and Jeanne T Paz
| Summary:
Chronic neural circuit hyperexcitability frequently emerges after brain injury, but endogenous mechanisms constraining runaway activity remain poorly understood. Here, we reveal that the adaptive immune system acts as a homeostatic brake on network excitability following traumatic brain injury (TBI). In mice, cortical trauma triggered a delayed infiltration of interferon-γ (IFNγ)–producing type 1 lymphocytes into the sensory thalamus. Rather than driving pathology, IFNγ signaling directly in neurons restricted thalamocortical network hyperexcitability. This protective axis was tonically regulated; depleting CD4⁺ T cells de-repressed local non-CD4⁺ type 1 lymphocytes, elevating IFNγ signaling and protecting from seizures. A single dose of exogenous IFNγ abolished hypersynchronous circuit bursting and rescued injury-induced seizure incidence, severity, and mortality, establishing a therapeutic framework for safeguarding circuit stability after brain injury.