Antiepileptogenesis by Transcranial Magnetic Stimulation

描述(申请人提供)：癫痫持续状态(SE)通常是癫痫发生的触发事件，是一系列神经元变化，导致异常兴奋并最终导致癫痫。癫痫的发生在很大程度上依赖于兴奋性突触强度的持续增强，这类似于实验性高频重复神经元刺激的长时程增强(LTP)。在这方面，我们建议研究经颅磁刺激(IMS)的抗癫痫潜力，IMS是一种重复激活神经元的非侵入性方法，作为一种新的癫痫治疗工具而受到关注。TMS吸引人的特性是它具有1)终止癫痫发作和2)导致突触强度持续下降的能力。后者的作用可能类似于LTP的抑制性对应的长期抑郁(LTD)。因此，我们的总体假设是，低频重复(RTMS)的抗惊厥和LTD样作用可以干扰SE触发的癫痫发生，阻止癫痫的表达。TMS基于电磁感应原理，其中颅内刺激电流是由强大的颅外磁场产生的。TMS安全、无痛且价格低廉。它的抗惊厥能力在少量的人体试验中得到证明，表明rTMS可以减少癫痫患者的癫痫发作频率。然而，人们对其作用机制知之甚少。因此，这一发展中的领域将受益于动物模型研究，以阐明TMS的基本生理学，并评估其治疗潜力。我们最近开发了同时进行TMS和脑电(EEG)的方法，并发现了新的有效的抗惊厥作用。我们现在建议使用大鼠海人藻酸(KA)SE模型来测试TMS的能力：1)停止SE，防止癫痫相关的神经元损伤；2)防止SE触发的癫痫发生。此外，为了评估TMS相关的细胞和分子作用机制，我们将通过将我们的方法扩展到体外海马片记录来测试低频rTMS是否可以诱导LTD。为了实现这些总体目标，我们将扩大我们的研究范围，包括体外和体外海马片记录。

DESCRIPTION (provided by applicant): Status epilepticus (SE) is often the triggering event for epileptogenesis, a sequence of neuronal changes that lead to abnormal excitation and ultimately to epilepsy. Epileptogenesis is dependent in large part on lasting enhancement of excitatory synaptic strength that is similar to the long-term potentiation (LTP) seen with experimental high frequency repetitive neuronal stimulation. In this regard, we propose to investigate the anti-epileptogenic potential of transcranial magnetic stimulation (IMS), a noninvasive method for repetitive neuronal activation that is coming to attention as a new therapeutic tool in epilepsy. The attractive properties of TMS are its ability to 1) terminate seizures and to 2) produce a lasting decrease in synaptic strength. The latter effect may be similar to the long-term depression (LTD) that is LTP's inhibitory counterpart. Accordingly, our overall hypothesis is that the anticonvulsive and LTD-like effects of low frequency repetitive (rTMS) can interfere with SE-triggered epileptogenesis and prevent the expression of epilepsy. TMS is based on the principle of electromagnetic induction where intracranial stimulating currents are generated by a strong extracranial magnetic field. TMS is safe, painless and inexpensive. Its anticonvulsive capacity is demonstrated in a small number of human trials showing a reduction seizure frequency reduction in epileptic patients treated with rTMS. However, its mechanism of action is poorly understood. Therefore, this developing field would benefit from animal model research for elucidation of basic TMS physiology, and for evaluation of its therapeutic potential. We recently developed methods for simultaneous TMS and electroencephalography (EEG) in seizing rats, and identified new potent anti-convulsive effect. We now propose to use the rat kainate (KA) SE model to test the capacity of TMS to 1) stop SE and prevent the seizure-associate neuronal injury, and 2) prevent SE-triggered epileptogenesis. Further, to evaluate the TMS-related cellular and molecular mechanisms of action, we will test whether low frequency rTMS can induce LTD by extending our methods to in vitro hippocampal slice recording. To achieve these overall goals, we will extend our studies to include in vitro and ex vivo hippocampal slice recordings.