Role of Akt and Mammalian Target of Rapamycin in Functional Outcome after Concussive Brain Injury in Mice

Abstract

Akt (protein kinase B) and mammalian target of rapamycin (mTOR) have been implicated in the pathogenesis of cell death and cognitive outcome after cerebral contusion in mice; however, a role for Akt/mTOR in concussive brain injury has not been well characterized. In a mouse closed head injury (CHI) concussion traumatic brain injury (TBI) model, phosphorylation of Akt (p-Akt), mTOR (p-mTOR), and S6RP (p-S6RP) was increased by 24 hours in cortical and hippocampal brain homogenates ( P < 0.05 versus sham for each), and p-S6RP was robustly induced in IBA-1 + microglia and glial fibrillary acidic protein-positive (GFAP +) astrocytes. Pretreatment with inhibitors of Akt or mTOR individually by the intracerebroventricular route reduced phosphorylation of their respective direct substrates FOXO1 ( P < 0.05) or S6RP ( P < 0.05) after CHI, confirming the activity of inhibitors. Rapamycin pretreatment significantly worsened hidden platform ( P < 0.01) and probe trial ( P < 0.05) performance in CHI mice. Intracerebroventricular administration of necrostatin-1 (Nec-1) before CHI increased hippocampal Akt and S6RP phosphorylation and improved place learning (probe trials, P < 0.001 versus vehicle), whereas co-administration of rapamycin or Akt inhibitor with Nec-1 eliminated improved probe trial performance. These data suggest a beneficial role for Akt/mTOR signaling after concussion TBI independent of cell death that may contribute to improved outcome by Nec-1.