Abstract
Temporal lobe epilepsy (TLE) is a chronic neurological disease affecting brain structures implicated in cognitive functions. The disease is manifested by the appearance of disabling, spontaneous, recurrent seizures caused by the hyper-excitability and hyper-synchronization of a more or less extensive group of neurons in the temporal lobe structures. Seizures are accompanied by neuronal death, gliosis and structural and synaptic reorganization. Sixty percent of patients do not respond to anti-epileptic drugs and the only curative intervention is the surgical resection of the epileptic focus. It is therefore urgent to better understand the mechanisms involved in pathogenesis in order to identify new therapeutic targets.It is now well documented that neuroinflammation is critically involved in this disease. Accumulated data suggest that microglia develops a dual profile, pro and anti-inflammatory, and that the balance between these two states determines the evolution of the disease. Using a TLE mouse model lacking T cells (CD3 -/- mouse), we observed a loss of the microglial anti-inflammatory response and an increase of neuronal death in the hippocampus together with an increase of spontaneous seizure frequency. Our working hypothesis is that, interactions between microglia and T cells drive a protective anti-inflammatory effect in the epileptic hippocampus. Regulatory T cells (Treg) have been shown to promote anti-inflammatory reactions in different models of CNS disorders. In preliminary experiments we therefore depleted Treg by administrating anti-CD25 antibodies during early epileptogenesis and we observed a loss of the microglial anti-inflammatory response and an increased neuronal death. We will confirm these results and test whether this treatment alters the development of seizure events. Eventually, we will assess whether microglial depletion phenocopies T cells depletion worsening TLE. These findings may allow the identification of new therapeutic targets to enhance the endogenous anti-inflammatory response and ultimately improve the treatment of ELT.