Development of NMDA Synapses in Rat Dysplastic Neurons

对于药物难治性癫痫患者，可以通过手术切除癫痫发作区域以减少局灶性癫痫发作。 局灶性癫痫皮质，与相邻皮质相比，包括在切除，有显着更多的迷失方向的神经元或皮质发育不良。 在来自癫痫病灶的人类发育不良皮质组织中，谷氨酸-NMDA受体具有与NR 1亚基物理共组装的NR 2B亚基，已知NR 1亚基形成超兴奋性NMDA受体复合物。 切除的癫痫发育不良皮质的研究表明，这些NMDA受体异常是由于蛋白质复合物的显着增加，整个长NMDA膜受体环相互作用。 现在，我们建议使用胎儿辐射大鼠模型皮质发育不良，以测试有关的膜和突触机制，在这些超兴奋性NMDA离子通道，导致局灶性皮质癫痫发作的儿童和成人的发展过程中的假设。 人类研究受到以下限制：没有正常对照组织，不知道何时以及何种类型的产前损伤发生，以及没有持续跟踪产后发育。 相比之下，与胎儿辐射大鼠的对照研究，我们将量化的“关键时期”时，谷氨酸NMDA受体开发异常永久的物理coassembly，有助于超兴奋性。 本研究的长期目标是研究大鼠大脑皮层中NMDA受体复合物的正常发育，以及产前伽马辐照损伤如何改变预期的神经元层压、神经元取向和膜受体蛋白的发育，这些蛋白有助于神经元过度兴奋。 同时，我们将研究聚集在NMDA受体上并有助于突触传递的突触后蛋白。 这些发现可能有助于设计新的治疗药物，靶向阻断1）NMDA受体中的特异性异常蛋白质共组装，或2）膜相关突触后蛋白。 这些药物可以成功地减少癫痫发生，而不会抑制或干扰大脑中正常的突触传递。

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.