Glutamate Receptors in Epilepsy: Group I mGluR-Mediated Epileptogenesis

Excerpt

Stimulation of group I mGluRs elicits ictal-like responses from normal quiescent hippocampal slices. Ictal-like responses once induced become persistent and show no fading even upon washout of the agonist. The conversion of normal neuronal activity to long-lasting epileptiform discharges resembles epileptogenesis and effects of group I mGluRs on hippocampal network provides a model for detailed studies of epileptogenesis. Experiments on the group I mGluR model reveal that epileptogenesis is sustained by specific long-lasting cellular responses (cellular plasticity). The latter include activation of a voltage-dependent cationic current and suppression of afterhyperpolarizations following action potentials. Induction of cellular plasticity (and epileptogenesis) requires synthesis of new proteins via local dendritic translation. The translation process is normally controlled by endogenous translation repressors including BC1 RNA and FMRP (fragile X mental retardation protein). Absence of FMRP causes fragile X syndrome (FXS) which is characterized by developmental mental retardation and enhanced susceptibility to epilepsy. Recent data indicate that group I mGluR-mediated translation is aberrantly enhanced in the absence of the repressor FMRP and that the enhanced translation constitutes a core co-morbidity mechanism of mental retardation and epilepsy observed in FXS. Thus, group I mGluRs represent a site of vulnerability and a potential therapeutic target against epilepsy.