Neurophysiological Study of CA1 Synaptic Reorganization

描述（由申请人提供）：癫痫是一种主要的神经系统疾病， 健康问题影响了大约300万美国人。尽管 流行和几十年的研究努力，我们对 难治性癫痫的细胞机制仍然有限。大部分 癫痫的研究一直集中在电生理学的后果， 急性癫痫发作导致发现了几种抗惊厥药， 目前可用。然而，我们对这些机制的了解有限， 癫痫的慢性改变阻碍了 真正的“抗癫痫药”。现在人们认识到反复发作 诱发人类颞叶边缘结构的形态学改变 叶癫痫和慢性动物模型的这种情况。这些 形态学改变包括苔藓纤维途径的发芽， 形成新的周期性兴奋性侧支， 齿状回过度兴奋拟议的研究调查了 令人兴奋的可能性，这种假定的癫痫细胞机制， 发芽引起的过度兴奋，是另一个主要因素， 脆弱的边缘结构，海马体的CA1区。我有 在4种慢性模型中获得了CA1区发芽的解剖学证据 因此，为本文所述的假设提供了理论基础。 提议作为这一新认识到的现象的功能后果， CA1神经元是未知的，我想扩展我的解剖学研究， 使用神经生理学技术来解决这个问题。的假设 这一补助金提案的延期没有改变， CA1区的突触重组是导致 该回路中的过度兴奋性增强了对进一步 癫痫发作我们在CA1锥体神经元的记录方面取得了进展，但我们 仍然需要确定解剖结构之间是否存在相关性， 红藻氨酸诱导的高兴奋性在脑内的分布 CA1区锥体神经元的电生理特性及解剖学意义 分布海人酸诱导的突触重组在CA 1区。 在获奖的前18个月，没有可用的海人酸 （全球短缺）。我们评估了毛果芸香碱模型， 虽然CA1突触重组发生，但它还不够强大， 与先前用红藻氨酸进行的实验相比，所提出的研究。作为 红藻氨酸在2000年5月上市，我们开始研究 兴奋过度和海马CA1区的发芽之间的联系。 2000年8月，我接受了UTHSCSA的一个职位，并于2000年10月搬家。 拟议的实验将更好地确定慢性 颞叶癫痫（TLE）的癫痫发生，并可能导致发展 治疗TLE的新药理学方法。为 MCSDA的教育部分，我现在参加药理学研讨会， UTHSCSA并选择Steven Mifflin博士作为我的新导师，因为他 丰富的脑切片神经生理学经验。我会投入至少75% 研究的努力，以及癫痫临床护理的剩余努力。

DESCRIPTION (provided by applicant): Epilepsy is a major neurologic public health problem that affects an estimated 3 million Americans. Despite its prevalence and several decades of research efforts, our understanding about the cellular mechanisms underlying intractable epilepsy remains limited. Most of the epilepsy research has been focused on the electrophysiological consequences of acute seizures leading to the discovery of several anticonvulsants that are currently available. However, our limited understanding about the mechanisms underlying the chronic alterations of epilepsy has hampered the development of true "anti-epileptic" drugs. It is now recognized that repeated seizures induced morphological alterations in the limbic structures of human temporal lobe epilepsy and in chronic animal models of this condition. These morphological alterations include sprouting of the mossy fiber pathway that forms new recurrent excitatory collaterals leading to a permanent hyperexcitability of the dentate gyrus. The proposed research investigates the exciting possibility that this putative cellular mechanism of epilepsy, sproutinginduced hyperexcitability, is a major contributor in another seizurevulnerable limbic structure, the CA1 region of the hippocampus. I have obtained anatomical evidence of sprouting in the CA1 region in 4 chronic models of epilepsy, thus, providing a rationale for the hypothesis described in this proposal. As the functional consequences of this newly recognized phenomenon in CA1 neurons are not known, I would like to extend my anatomical studies by using neurophysiological techniques to address this question. The hypothesis of this grant proposal extension has not changed and is that seizureinduced synaptic reorganization in the CA1 region is a mechanism that leads to hyperexcitability in this circuitry enhancing the susceptibility to further seizures. We have made progress in recording from CA1 pyramidal neurons, but we still need to determine whether there is a correlation between the anatomical distribution of Kainic acid induced hyperexcitability in the electrophysiological properties of CA1 pyramidal neurons and the anatomical distribution of Kainic acid induced synaptic reorganization in the CA1 region. During the first 18 months of the award, there was no Kainic acid available (worldwide shortage). We evaluated the Pilocarpine model, and we determined that although CA1 synaptic reorganization occurs, it was not robust enough for the proposed studies as compared to prior experiments with Kainic acid. As Kainic acid became available in May 2000, we began to examine the relationship between hyperexcitability and sprouting in the CA1 region of the hippocampus. In August 2000, I accepted a position in UTHSCSA, and I moved in October 2000. The proposed experiments will better define the mechanisms of chronic epileptogenesis in Temporal Lobe Epilepsy (TLE) and may lead to the development of novel pharmacological approaches for the treatment of TLE. For the Educational component of the MCSDA, I now attend the pharmacology seminars at UTHSCSA and have selected Dr. Steven Mifflin as my new mentor owing to his extensive experience in brain slice neurophysiology. I will devote at least 75% of effort to research, and the remaining effort for clinical care in Epilepsy.