Metabotropic glutamate receptors and epilepsy

Metabotropic glutamate receptors (mGluRs) play an important role in the initiation of ictal discharges by participating in the interictal-ictal transition, and may play a crucial role in recruiting normal brain tissue into synchronized discharges, thereby facilitating propagation of seizure activity. In this article we present a review of mGluRs and epilepsy studies. Structural features of mGluRs offer multiple possibilities for synthetic compounds to modulate their activity, and for many reasons these compounds are good candidates for therapeutic applications. Group I mGluRs enhance excitatory transmission as much as groups II and III mGluRs can modulate those effects. Finally, main avenues to induce epileptogenesis are considered: activation of Ca2+ channels and Ca2+/CaMKII cascade, overexpression of AMPA and/or KA receptors, enhanced NMDARs function, activation of protooncogenes leading to a steady epileptogenic state, enhancement of INaP currents, blockade of A and/or M K+ currents, calcium channelopathies, diminished number of GABARs or functions, and down-regulation of glutamate transporters. Deregulation of mGluR signaling functions including deficits in groups II and III mGluRs or hyperactivation of group I mGluRs may occur in some forms of epilepsy, therefore targeting these mechanisms with specific pharmacological tools could provide new developments for original therapeutic approaches.