Activation of group I metabotropic glutamate receptors (mGluRs) mediates a second-messenger cascade of events potentially leading to long-lasting cellular and network changes in hippocampal excitability. Due to their perisynaptic localization, the group I mGluRs are recruited in particular at times of high-intensity neuronal firing and enhanced glutamate release. We have shown that transient selective activation of group I mGluRs can initiate an epileptogenic process in which the hippocampal circuit remains persistently predisposed to express ictal-length discharges. The induction process underlying this hippocampal epileptogenesis is protein synthesis dependent and driven primarily by the activation of mGluR5. A novel current discovered by the Wong lab underlies the expression of these ictaform discharges, which seems to be dependent on ongoing activation of mGluR1. Neither NMDA activation nor activation of protein kinase C is necessary for either induction or expression of these network bursts.
One might ask, if the hippocampus is so epilepsy-prone, what prevents most individuals from developing mGluR-induced seizures and epilepsy? The answer appears to be that normal individuals have built-in endogenous regulators that clamp down on group I mGluR-driven protein synthesis, thereby preventing excessive pathologic excitation from occurring. Experiments in mutant mice have uncovered the important roles of mRNA repressors, such as the fragile X mental retardation protein, in the regulation of the mGluR-induced excitatory network effects. Indeed, knockout of mGluR5 can prevent development of the fragile X phenotype, revealing the important role of group I mGluR activation in the pathogenesis of fragile X syndrome. Clinical trials with mGluR5 antagonists are currently underway.
It is likely that individuals with hyperexcitable group I mGluRs, either due to direct receptor mutations or defects in downstream regulators, are more susceptible to the development of posttraumatic or post-stroke epilepsy. Further studies in this arena hold promise for the prevention of epileptogenesis in these subgroups.
(Excerpted from upcoming chapter by L. R. Merlin and R. K. S. Wong in Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels, J. L., Avoli, M., Rogawski, M. A., Olsen, R. W., and Delgado-Escueta, A. V., eds), to be published by Oxford University Press; mini-article in press in Epilepsia)
Merlin, L. R., and Wong, R. K. S. (1997). Role of group I metabotropic glutamate receptors in the patterning of epileptiform activities in vitro. J. Neurophysiol. 78, 539-544.
Merlin, L. R., Bergold, P. J., and Wong, R. K. S. (1998). Requirement of protein synthesis for group I mGluR-mediated induction of epileptiform discharges. J. Neurophysiol. 80, 989-993.
Merlin, L. R. (1999). Group I mGluR-mediated silent induction of long-lasting epileptiform discharges. J. Neurophysiol. 82, 1078-1081.
Galoyan, S. M., and Merlin, L. R. (2000). Long-lasting potentiation of epileptiform bursts by group I mGluRs is NMDA receptor independent. J. Neurophysiol. 83, 2463-2467.
Merlin, L. R. (2002). Differential roles for mGluR1 and mGluR5 in the persistent prolongation of epileptiform bursts. J. Neurophysiol. 87, 621-625.
Rico, M. J., and Merlin, L. R. (2004). Evidence that phospholipase D activation prevents group I mGluR-induced persistent prolongation of epileptiform bursts. J. Neurophysiol. 91, 2385-2388.
Huszár, P., and Merlin, L. R. (2004). Contribution of GABAB receptor-mediated inhibition to the expression and termination of group I mGluR-induced ictaform bursts. Epilepsy Res. 61, 161-165.
Cuellar, J. C., Griffith, E. L., and Merlin, L. R. (2005). Contrasting roles of protein kinase C in induction versus suppression of group I mGluR-mediated epileptogenesis in vitro. J. Neurophysiol. 94, 3643-3647.
Merlin, L. R. (2009). The fragile X mental retardation protein: a valuable partner in the battle against epileptogenesis. Epilepsy Curr. 9, 116-118.
Fuortes, M. G., Rico, M. J., and Merlin, L. R. (2010). Distinctions between persistent and reversible group I mGluR-induced epileptiform burst prolongation. Epilepsia (in press)
- Chair, Associated Medical Schools of NY (AMSNY) Committee for Medical Education in Neuroscience
- Member, American Academy of Neurology (AAN) Undergraduate Education Subcommittee
- Member, AAN Dreifuss-Penry Epilepsy Award Selection Committee
- Member, American Epilepsy Society (AES) Epilepsy Currents Editorial Board
- Member, National Board of Medical Examiners (NBME) Committee for Standard Setting of the Clinical Neurology Subject Examination