Abstracts

Rationale: Previously we have shown that scar astrocytes found in hippocampal sclerosis (HS) in MTLE revealed increased phosphorylation of ribosomal protein S6 (pS6) (Mikell et al., 2009). In order to elucidate mechanisms of mTOR cascade activation in HS, we studied mTOR cascade in the development of the gliotic scar emerging after neuronal loss in a pilocarpine model of epilepsy in rats. Methods: We used immunohistochemistry and western blotting to evaluate levels of phosphorylated and non-phosphorylated downstream components of mTOR, p70 S6K, S6 and 4EB-P1, in a pilocarpine-induced model of epilepsy in rats and in surgically resected hippocampi in patients with medically intractable MTLE. Results: Two brain areas in pilocarpine treated rats usually revealed severe neuronal damage and accompanying astrogliosis: hippocampus and piriform/entorhinal cortex. In the first two weeks after insult, reactive astrocytes bordering the damaged areas expressed high levels of pS6. In one month after insult, only a few astrocytes bordering this area were pS6 immunopositive. Later on, when the glial scar began to form, gliotic astrocytes did not show activation of mTOR pathway. Thus in 3, 6 months and in 1.2 years (the latest time studied) scar astrocytes did not show mTOR activation and only some neurons were pS6 immunopositive. In all studied cases of human HS, scar astrocytes revealed high levels of pS6 and 4EB-P1. Conclusions: Based on the known data about the kinetics of mTOR activation, we argue that HS in surgically resected cases of MTLE is not a static phenomenon finalizing neuronal demise. In contrast to the traditional gliotic scar, in HS, there are some ongoing cellular processes that result in mTOR pathway activity.