The Medial Entorhinal Cortex and Temporal Lobe Epilepsy

描述（由申请人提供）：颞叶癫痫（TLE）是一种破坏性的癫痫发作疾病，难以用现有的抗癫痫药物控制。为了更好地了解癫痫发生的过程和开发用于管理TLE的创新治疗方法，已经开发了表现出这种癫痫发作病症的特征的动物模型：对CNS的初始损伤，可变的潜伏期，以及最终发展为颞叶起源的自发性癫痫发作。本提案的总体目标是确定内侧内嗅皮层（mEC）在TLE的红藻氨酸模型中慢性癫痫发展中的作用。该提案将测试的假设，改变电路和变化的兴奋性突触功能的神经元在mEC的浅层的贡献，至少部分地，超兴奋性和同步化的mEC海马（HC）神经回路中的红藻氨酸模型TLE。将通过使用全细胞膜片钳技术在从对照大鼠和经历红藻氨酸诱导的TLE癫痫持续状态（SE）模型的那些大鼠获得的组合mEC-HC脑切片制备物中测试该假设（目标2和3）实现以下具体目标：1）比较和对比动力学，短期塑性，和药理学调节从正常动物获得的脑切片中mEC的第III层PYR细胞和第II层STEL细胞中的兴奋性突触后电流（EPSC）。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进行性变化。确定红藻氨酸诱导SE后，第II层STEL细胞中EPSC的动力学、短期可塑性和药理学调节是否随时间变化。3)确定KA处理后STEL细胞之间单突触连接的概率是否增加。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回路的功能影响。这些实验将为未来治疗药物耐药性癫痫的治疗干预措施的发展奠定基础。

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.