Neurophysiological Study of CA1 Synaptic Reorganization

CA1突触重组的神经生理学研究

• 批准号: 6438879
• 负责人: Jose E Cavazos
• 金额: $ 14.27万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2004-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6438879
• 关键词: cellular pathology; epilepsy; hippocampus; histochemistry /cytochemistry; kainate; laboratory rat; neuroanatomy; neuronal guidance; neurons; neurophysiology; partial seizure; pathologic process; pilocarpine; pyramidal cells; synapses; temporal lobe /cortex disorder; tissue /cell culture

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.

描述（申请人提供）：癫痫是主要的神经系统公众 影响约300万美国人的健康问题。尽管有它 流行率和数十年的研究工作，我们对 顽固性癫痫的基础机制仍然有限。大多数 癫痫研究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 目前可用。但是，我们对机制的有限理解 癫痫的长期改变的根本改变阻碍了 真正的“抗癫痫药”药物。现在认识到重复的癫痫发作 人类时间的边缘结构的诱导形态变化 叶癫痫和这种情况的慢性动物模型。这些 形态学的改变包括苔藓纤维途径的发芽 形成新的复发性兴奋性侧支，导致永久性 齿状回的过度刺激性。拟议的研究调查了 令人兴奋的可能性是这种推定的癫痫的细胞机制， 发芽诱导的过度兴奋性是另一个的主要贡献者 可杀伤性的边缘结构，海马的CA1区域。我有 在4个慢性模型中获得了在CA1地区发芽的解剖学证据 因此，癫痫为此提供了理由 提议。作为这种新认识的现象的功能后果 CA1神经元尚不清楚，我想通过 使用神经生理技术来解决这个问题。假设 该赠款提案扩展未改变，是扣押诱导的 CA1区域中的突触重组是一种导致的机制 该电路中的过度兴奋性增强了进一步的敏感性 癫痫发作。我们从CA1锥体神经元录制方面取得了进展，但是我们 仍然需要确定解剖学之间是否存在相关性 海藻酸的分布在 CA1锥体神经元和解剖学的电生理特性 海藻酸诱导的CA1区域突触重组的分布。 在奖励的前18个月中，没有迦酸可用 （全球短缺）。我们评估了Pilocarpine模型，并确定了 尽管发生了CA1突触重组，但它不足以适应 与先前的海藻酸实验相比，提出的研究。作为 海藻酸于2000年5月开始使用，我们开始检查这种关系 在海马的CA1区域中过度兴奋和发芽之间。 2000年8月，我接受了UTHSCSA的职位，并于2000年10月搬家。 提出的实验将更好地定义慢性的机制 颞叶癫痫（TLE）中的癫痫发生，可能导致发展 用于治疗TLE的新型药理方法。为了 MCSDA的教育部分，我现在参加了在药理学研讨会上 UTHSCSA并选择了史蒂文·米夫林（Steven Mifflin）博士作为我的新导师 大脑切片神经生理学的丰富经验。我将至少投入75％ 研究的努力以及癫痫临床护理的剩余努力。