Modulating hippocampal neurogenesis to restore learning and memory in mesial temporal lobe epilepsy. (360G-Wellcome-099816_Z_12_A)

Learning and memory dysfunction is the commonest neuropsychological effect of mesial temporal lobe epilepsy (mTLE). Because the underlying neurobiology is poorly understood, there are no pharmacological strategies to restore learningand memory function. Neurogenesis in the adult dentate gyrus is important for allocentric hippocampal learning, is impaired in chronic mTLE due to chronic neuroinflammation, and we have recently shown thatrestoring neurogenesis in animal models returns allocentric learning to normal. Using 30 cultures of sclerotic hippocampus from epilepsy surgery patients we also show that this antineurogenic effect is Q£!1!y mediated via IL-1beta release. Cytokines released into the stem cell microenvironment from astrocytes, neurons and microglia are key modulators of neurogenesis under normal and neuroinflammatory states and are also primed by the complement system. Status epilepticus induced epigenetic modification of hippocampal neural stem cells also appears to play a role bothin normal and in chronically altered neurogenesis in mTLE. Our objectives are to examine the role of cytokines, the complement system and epigenetic modification in generating and maintaining the anti-neurogenic niche in animal models and human mTLE, and whether these affect hippocampal learning, in order to identify drug targets for treating cognitive impairment in human mTLE.