Neurophysiological Study of CA1 Synaptic Reorganization

描述(申请人提供)：癫痫是一种主要的神经科疾病 健康问题，估计有300万美国人受到影响。尽管它的 流行率和几十年的研究努力，我们对 顽固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后果上。 急性癫痫发作导致发现了几种抗惊厥药物 目前可用。然而，我们对这种机制的了解有限 癫痫的慢性改变阻碍了癫痫的发展 真正的“抗癫痫”药物。现在人们认识到，反复癫痫发作 诱发的人颞叶边缘结构的形态改变 脑叶癫痫和慢性动物模型中的这种情况。这些 形态改变包括苔藓纤维通路的萌发 形成新的经常性兴奋性侧支，导致永久性 齿状回的过度兴奋性。拟议的研究调查了 令人兴奋的可能性是癫痫的这种假定的细胞机制， 萌芽诱导的过度兴奋，是另一种 癫痫易发作的边缘结构，即海马区的CA1区。我有过 4种慢性模型CA1区发芽的解剖学证据 因此，为本文件中描述的假设提供了一个理论基础 求婚。作为这一新发现的现象的功能后果， CA1神经元是未知的，我想通过以下方式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。的假说 这项拨款提议的延期并没有改变，而且是由 CA1区的突触重组是一种导致 这一回路中的过度兴奋性增加了对进一步 癫痫发作。我们在记录CA1锥体神经元方面取得了进展，但我们 仍然需要确定解剖学上的 红藻氨酸诱导的兴奋性超敏反应在大鼠脑内的分布 CA1区锥体神经元的电生理特性及解剖学研究 红藻氨酸在CA1区的分布诱导突触重组。 在获奖的前18个月，没有红藻氨酸可用。 (全球短缺)。我们评估了匹罗卡品模型，并确定了 尽管发生了CA1突触重组，但它还不够强大 拟议的研究与之前的红藻氨酸实验进行了比较。AS 2000年5月，红藻氨酸问世，我们开始研究两者之间的关系 在过度兴奋和海马区CA1区发芽之间。 2000年8月，我接受了UTHSCSA的一个职位，并于2000年10月搬家。 拟议中的实验将更好地定义慢性病的机制 颞叶癫痫(TLE)的致痫机制及其可能的发病机制 介绍了治疗TLE的新的药理方法。对于 作为MCSDA的教育组成部分，我现在参加了 UTHSCSA并选择Steven Mifflin博士作为我的新导师 具有丰富的脑片神经生理学经验。我会投入至少75% 对研究的努力，以及对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.