Tumor necrosis factor alpha and Fas receptor contribute to cognitive deficits independent of cell death after concussive traumatic brain injury in mice

Tumor necrosis factor alpha (TNF alpha) and Fas receptor contribute to cell death and cognitive dysfunction after focal traumatic brain injury (TBI). We examined the role of TNF alpha/Fas in postinjury functional outcome independent of cell death in a novel closed head injury (CHI) model produced with weight drop and free rotational head movement in the anterior-posterior plane. The CHI produced no cerebral edema or blood-brain barrier damage at 24 to 48 hours, no detectable cell death, occasional axonal injury (24 hours), and no brain atrophy or hippocampal cell loss (day 60). Microglia and astrocytes were activated (48 to 72 hours). Tumor necrosis factor-alpha mRNA, Fas mRNA, and TNF alpha protein were increased in the brain at 3 to 6 hours after injury (P < 0.001 versus sham injured). In wild-type (WT) mice, CHI produced hidden platform (P = 0.009) and probe deficits (P = 0.001) in the Morris water maze versus sham. Surprisingly, injured TNF alpha/Fas knockout (KO) mice performed worse in hidden platform trials (P = 0.036) but better in probe trials than did WT mice (P = 0.0001). Administration of recombinant TNF alpha to injured TNF alpha/Fas KO mice reduced probe trial performance to that of WT. Thus, TNF alpha/Fas influence cognitive deficits independent of cell death after CHI. Therapies targeting TNF alpha/Fas together may be inappropriate for patients with concussive TBI. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 778-789; doi:10.1038/jcbfm.2010.172; published online 13 October 2010