Developmental Plasticity and Chronic Epilepsy

发育可塑性和慢性癫痫

• 批准号: 6684786
• 负责人: John William Swann
• 金额: $ 35.15万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684786
• 关键词: AMPA receptors; NMDA receptors; brain electrical activity; dentate gyrus; developmental neurobiology; disease /disorder etiology; disease /disorder model; electroencephalography; electron microscopy; electrophysiology; epilepsy; granule cell; hippocampus; ion channel blocker; laboratory rat; model design /development; mossy fiber; neocortex; neural plasticity; neural transmission; neuropathology; pathologic process; tetrodotoxin; voltage /patch clamp; western blottings

DESCRIPTION (provided by applicant): Disruptions in neuronal activity are known to occur in and around a wide variety of malformations in the infant brain. Recurrent seizures often originate from these malformed lesions. The goal of this research program is to further our understanding of how localized interruptions in neuronal activity may contribute to the formation of epileptic foci. For the first time, our laboratory has shown that a life long epilepsy is produced when neuronal activity is abolished by local infusion of the voltage gated sodium channel antagonist, TTX, into the immature hippocampus. EEG recordings have shown that the infused hippocampus is an epileptic focus and abnormal synchronized network discharges are recorded in area CA3 of hippocampal slices taken from these animals. Experiments have examined the possibility that CA3 network hyperexcitability is the result of sprouting and hyperinnervation of CA3 pyramidal cells by local recurrent excitatory axon collaterals. However, results do not favor this hypothesis. On the other hand, results demonstrate a significant increase and alterations in the expression of subunits for both AMPA and NMDA receptors. In proposed experiments, this new model of early-onset epilepsy will be further characterized. Included, are studies demonstrating that TTX-infusion in developing neocortex can also produce epileptic loci. The remaining experiments focus on a single unifying hypothesis that chronic activity blockade results in dramatic changes in subunit composition of glutamatergic synapses and that these changes result in unusually large and prolonged AMPA and NMDA receptor mediated EPSPs that contribute to synchronized network discharging and the chronic epilepsy observed in these animals. Planned electrophysiolgical and biochemical experiments will characterize alterations in AMPA and NMDA receptor mediated synaptic transmission during activity blockade. Intrahippocampal infusion of AMPA and NMDA receptor antagonists is expected to produce similar changes at glutamatergic synapses and epilepsy. Since there are so few animal models of early-onset epilepsy, the studies proposed here offer a unique opportunity to further an understanding of the biological origins of seizure disorders in infancy.

描述（由申请人提供）：已知神经元活性的破坏会发生在婴儿大脑中及周围的各种畸形。复发性癫痫发作通常源自这些畸形的病变。该研究计划的目的是进一步了解神经元活动中局部中断如何有助于形成癫痫灶的形成。我们的实验室第一次表明，当局部输注电压门控钠通道拮抗剂TTX局部输注到未成熟的海马时，会产生寿命长的癫痫。脑电图记录表明，注入的海马是一种癫痫焦点，并且在从这些动物那里取的海马切片的CA3区域记录了异常的同步网络放电。实验检查了CA3网络过度兴奋性是通过局部复发性兴奋性轴突侧支对CA3锥体细胞发芽和过度连接的结果。但是，结果不利于这一假设。另一方面，结果表明AMPA和NMDA受体的亚基表达的显着增加和改变。在拟议的实验中，将进一步表征这种新的早期癫痫模型。包括的研究表明，发展新皮层的TTX灌注也可以产生癫痫基因座。其余的实验集中于一个单一的统一假设，即慢性活动阻滞导致谷氨酸能突触的亚基组成的巨大变化，并且这些变化导致异常大，延长的AMPA和NMDA受体介导的EPSP，导致了同步网络排放和慢性癫痫发作的EPSP在这些动物中。计划的电生理和生化实验将表征活动阻滞期间AMPA和NMDA受体介导的突触传播的改变。预计对AMPA和NMDA受体拮抗剂的汉皮门内输注有望在谷氨酸能突触和癫痫病上产生类似的变化。由于早期发作癫痫的动物模型很少，因此这里提出的研究提供了一个独特的机会，可以进一步了解婴儿期癫痫发作疾病的生物学起源。