The Medial Entorhinal Cortex and Temporal Lobe Epilepsy

内侧内嗅皮层和颞叶癫痫

• 批准号: 6708388
• 负责人: Karen S Wilcox
• 金额: $ 28.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6708388
• 关键词: NMDA receptors; behavior test; brain electrical activity; entorhinal cortex; epilepsy; histochemistry /cytochemistry; laboratory rat; neural plasticity; neurons; neurophysiology; synapses; temporal lobe /cortex; tissue /cell culture; voltage /patch clamp

DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) is a devastating type of seizure disorder that is difficult to control with existing antiepileptic drugs. In order to better understand the process of epileptogenesis and to develop innovative therapeutic approaches for the management of TLE, animal models have been developed that exhibit the hallmarks of this seizure disorder: an initial insult to the CNS, a variable latent period, and the eventual development of spontaneous seizures of temporal lobe origin. The overall goal of this proposal is to determine the role of the medial entorhinal cortex (mEC) in the development of chronic epilepsy in the kainic acid model of TLE. This proposal will test the hypothesis that altered circuitry and changes in excitatory synaptic function of neurons in the superficial layers of the mEC contribute, at least in part, to hyperexcitability and synchronization in the mEC-hippocampal (HC) neural circuit in the kainic acid model of TLE. This hypothesis will be tested by using the whole cell patch clamp technique in the combined mEC-HC brain slice preparation obtained from control rats and those subjected to the kainic acid-induced status epilepticus (SE) model of TLE (Aims 2 & 3) to perform the following specific aims: 1) Compare and contrast the kinetics, short-term plasticity, and pharmacological modulation of excitatory postsynaptic currents (EPSCs) in Layer III PYR cells and Layer II STEL cells of the mEC in brain slices obtained from normal animals. 2) Determine if there are progressive changes in the electroresponsive membrane properties of STEL cells in the mEC at various time points following kainate-induced SE. Determine if there are alterations in the kinetics, short-term plasticity, and pharmacological modulation of EPSCs in Layer II STEL cells as a function of time following kainate-induced SE. 3) Determine if there is an enhanced probability of monosynaptic connections between STEL cells following KA treatment. By surveying the development of functional changes in principle neurons of the mEC in an animal model of TLE, we will gain insight into why PYR cells degenerate, why STEL cells become hyperexcitable, and what the functional impact of these changes are for the mEC-HC circuit. These experiments will set the stage for the development of future therapeutic interventions for the treatment of pharmacoresistant epilepsy.

描述（由申请人提供）：颞叶癫痫（TLE）是一种破坏性的癫痫疾病，现有的抗癫痫药物难以控制。为了更好地了解癫痫发生的过程并开发治疗 TLE 的创新治疗方法，我们开发了动物模型，这些模型表现出这种癫痫疾病的特征：最初对中枢神经系统的损害、可变的潜伏期以及最终的癫痫发作。颞叶起源的自发性癫痫发作的发展。该提案的总体目标是确定内侧内嗅皮层 (mEC) 在 TLE 红藻氨酸模型中慢性癫痫发展中的作用。该提案将检验以下假设：mEC 浅层神经元的回路改变和兴奋性突触功能的变化至少部分地导致红藻氨酸模型中 mEC-海马 (HC) 神经回路的过度兴奋和同步的 TLE。该假设将通过使用全细胞膜片钳技术在从对照大鼠和接受红藻氨酸诱导的 TLE 癫痫持续状态 (SE) 模型的大鼠获得的组合 mEC-HC 脑切片制剂中进行测试（目标 2 和 3）执行以下具体目标：1）比较和对比第三层 PYR 细胞和第二层 STEL 细胞中兴奋性突触后电流（EPSC）的动力学、短期可塑性和药理调节。从正常动物获得的脑切片中的 mEC。 2) 确定在红藻氨酸诱导 SE 后的不同时间点，mEC 中 STEL 细胞的电响应膜特性是否存在渐进性变化。确定第二层 STEL 细胞中 EPSC 的动力学、短期可塑性和药理学调节是否随红藻氨酸诱导 SE 后的时间发生变化。 3) 确定 KA 处理后 STEL 细胞之间单突触连接的可能性是否增加。通过调查 TLE 动物模型中 mEC 主要神经元功能变化的发展，我们将深入了解为什么 PYR 细胞退化、为什么 STEL 细胞变得过度兴奋，以及这些变化对 mEC-HC 的功能影响是什么电路。这些实验将为未来治疗耐药性癫痫的治疗干预措施的开发奠定基础。