We are studying the processes that cause the normal brain to become epileptic. There may be multiple mechanisms involved. We study seizures triggered by the activation of one kind of neuronal receptor, metabotropic glutamate receptors (mGluRs), in hippocampal neurons of mice. When hippocampal neurons are exposed to chemicals which stimulate only group 1 mGluRs, the neurons fire epileptiform discharges (which trigger seizures). We and others have shown that this occurs only if new proteins are being synthesized.
Our results show that intense stimulation of the glutamate synapses cannot elicit the group 1 mGluR-mediated epileptogenesis in normal mice. Apparently, neurons of normal mice have a mechanism to protect them from seizures. In contrast, using tissue from Fragile X knockout mice, this same stimulation easily and consistently elicited robust seizure activity.
We are testing the theory that in normal mice, the protein FMRP suppresses group 1 mGluR-dependent epileptogenesis by suppressing the translation of one or more proteins which are involved in triggering seizures. Our experiments will evaluate whether the function of group 1 mGluRs is exaggerated in neurons in the cortex of Fragile X knockout mouse. We plan to extend our studies to evaluate whether abnormalities in mGluR function can also affect other basic brain functions involved in learning and memory.