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The Medial Entorhinal Cortex and Temporal Lobe Epilepsy

内侧内嗅皮层和颞叶癫痫

基本信息

批准号：
7192406
负责人：
Karen S Wilcox
金额：
$ 23.65万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-03-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7192406
关键词：
Action Potentials Animal Model Animals Antiepileptic Agents Attention Axon Brain Cells Cellular Morphology Chronic Cognitive Condition Development Epilepsy Epileptogenesis Excitatory Synapse Exhibits Failure Frequencies Future Goals Hippocampus (Brain)Human Kainic Acid Kinetics Knowledge Learning Link Location Medial Mediating Membrane Memory Modeling N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurons Patch-Clamp Techniques Perforant Pathway Pharmacology Physiological Physiology Play Preparation Probability Process Property Pyramidal Cells Rattus Research Research Personnel Role Seizures Slice Solutions Staging Status Epilepticus Surveys Synapses Synaptic Transmission Synaptic plasticity Techniques Temporal Lobe Temporal Lobe Epilepsy Testing Therapeutic Therapeutic Intervention Time Ursidae Family Week axonal sprouting base biocytin cell type entorhinal cortex excitatory neuron innovation insight interest kainate neural circuit neurotransmission postsynaptic presynaptic programs receptor research study stellate cell synaptic function

项目摘要

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障碍，现有的抗癫痫药物难以控制。为了更好地了解癫痫的发生过程并开发治疗TLE的创新方法，已开发出具有这种癫痫障碍特征的动物模型：最初对中枢神经系统的侮辱，可变的潜伏期，以及最终起源于颞叶的自发性癫痫发作的发展。这项建议的总体目标是确定内侧内嗅皮层(MEC)在红藻氨酸TLE模型慢性癫痫发展中的作用。这一建议将检验一种假说，即在红藻氨酸TLE模型中，MEC浅层神经元的兴奋性突触功能的改变至少部分地有助于MEC-海马(HC)神经回路的超兴奋性和同步性。利用全细胞膜片钳技术在正常大鼠和红藻氨酸诱导的TLE癫痫持续状态(SE)模型大鼠的MEC-HC联合脑片上验证这一假说，以实现以下特定目的：1)比较和对比正常动物脑片中MEC的兴奋性突触后电流(EPSCs)的动力学、短期可塑性和药物调节。2)确定红藻氨酸诱导的SE后不同时间点MEC中STEL细胞的电反应膜特性是否有进行性变化。确定在红藻氨酸诱导的SE后，第二层STEL细胞中EPSCs的动力学、短期可塑性和药物调节是否随着时间的变化而变化。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。通过观察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PYR细胞为什么退化，为什么STEL细胞变得过度兴奋，以及这些变化对MEC-HC回路的功能影响。这些实验将为未来治疗耐药癫痫的治疗干预措施的发展奠定基础。