In patients with medically intractable epilepsy, the region of seizure onset can be surgically removed to reduce focal seizures. The focal epileptic cortex, compared to adjacent cortex included in the resection, has significantly more disoriented neurons or cortical dysplasia. In human dysplastic cortical tissue from the epileptic focus, glutamate-NMDA receptors have the NR2B subunit physically coassembled with the NR1 subunit, which has been known to form a hyperexcitable NMDA receptor complex. Studies of resected epileptic dysplastic cortices have revealed that these NMDA receptor abnormalities are attributable to significant increases in protein complexes, which interact throughout the long NMDA membrane receptor loops. We now propose to use the fetal radiated rat model of cortical dysplasia to test hypotheses regarding the membrane and synaptic mechanisms during development of these hyperexcitable NMDA ion channels that cause focal cortical seizures in both children and adults. Human studies are limited by not having normal control tissue, by not knowing when and what type of prenatal damage occurred, and by not following postnatal development consistently. By contrast, with the well-controlled studies in fetal radiated rats we will quantify the """"""""critical periods"""""""" when the glutamate NMDA receptor develops anomalous permanent physical coassembly that contributes to hyperexcitability. The long term objectives of this research are to study the normal development of the NMDA receptor complex in the rat cerebral cortex and how prenatal insults by gamma irradiation alter the development of the expected neuronal laminations, neuron orientations, and membrane receptor proteins that contribute to neuronal hyperexcitability. Simultaneously, we will study the postsynaptic proteins that cluster at the NMDA receptors and contribute to synaptic transmission. These findings may aid in designing new therapeutic agents targeted for blocking 1) only specific aberrant protein coassemblies in the NMDA receptor, or 2) in the membrane-associated postsynaptic proteins. Such drugs could successfully decrease epileptogenesis without depressing or interfering with normal synaptic transmission in the brain.
| Babb, Thomas L; Mikuni, Nobuhiro; Najm, Imad et al. (2005) Pre- and postnatal expressions of NMDA receptors 1 and 2B subunit proteins in the normal rat cortex. Epilepsy Res 64:23-30 |
