Abstracts

Rationale: Reactive astrogliosis is a feature of the brain response to virtually all insults, including trauma, infarction, seizures, and infection. Functional abnormalities in reactive astrocytes, especially defects in potassium and glutamate uptake, appear to contribute to continuing neurologic deficits and possibly seizures following brain injury; therefore reactive astrocytes have been proposed as a therapeutic target in epilepsy. We have previously shown activation of the mammalian target of rapamycin (mTOR) cascade in the characteristic astrogliosis of tuberous sclerosis complex (TSC.) We sought to determine whether mTOR activation was a general feature of reactive astrogliosis. Methods: To assess mTOR activation in reactive astrogliosis, we performed immunostaining for downstream mTOR cascade components (phospho-S6) in tissue from humans with mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS), as well as multiple rat models of reactive astrogliosis (status epilepticus, trauma, ischemia.) We also assessed single-astrocyte glutamate and potassium uptake using patch clamp electrophysiology. Results: Here, we demonstrate activation of the mTOR cascade in astrocytes in all tested models of reactive astrogliosis, as well as human hippocampus from patients with MTLE. In an acute trauma model, infusion of rapamycin limited astrogliosis, and limited physiologic changes in potassium and glutamate uptake by patch clamp. Conclusions: The mTOR inhibitor rapamycin ameliorates reactive astrogliosis, suggesting that the mTOR cascade is a prospective therapeutic target.