Pathophysiology of Developing Dysplastic Human Cortex

人类皮质发育不良的病理生理学

基本信息

  • 批准号:
    7049843
  • 负责人:
  • 金额:
    $ 31.29万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1999
  • 资助国家:
    美国
  • 起止时间:
    1999-07-01 至 2009-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Resective neurosurgery is a frequent treatment for children with therapy-resistant epilepsy. About half of surgical cases have cortical dysplasia (CD), consisting of cortical dyslamination, heterotopic neurons, and dysmorphic cytomegalic neurons and balloon cells. The others have non-CD pathologies such as infarcts and Rasmussen syndrome. The goals of this research project are to examine the electrophysiologic and anatomic properties of cells in pediatric CD tissue to discern mechanisms that lead to epileptogenesis. In the previous funding period, we found that cytomegalic neurons displayed increased voltage-gated calcium currents, and cytomegalic neurons and about 30% of pyramidal neurons showed decreased Mg++ sensitive NMDA receptors similar to immature cortex. Balloon cells did not display active membrane properties or synaptic activity. In Preliminary studies, we also found that severe CD has other immature features. These include more GABA than glutamate spontaneous synaptic currents and terminals, greater layer 1 evoked GABA-mediated currents, GABA-A receptors with depolarized reversal potentials, longer GABA-A receptor decay time constants, and more interneurons than expected including recently discovered cytomegalic GABA neurons. These findings lead us to hypothesize that severe CD consists of a proportion of cells that retain immature GABA signaling properties interacting with normal mature-like pyramidal cells to produce "pro-epileptic" conditions and seizures. This renewal will address this hypothesis by determining in severe CD if: 1) Synaptic signaling is similar to immature cortex with GABA (not glutamate) as the predominant neurotransmitter; 2) GABAA receptors on cytomegalic and some pyramidal neurons show immature characteristics, such as depolarized reversal potentials; 3) Enhancement of GABA function from GABA altering medications are excitatory and "pro-epileptic"; and 4) Interneurons display immature characteristics associated with spontaneous rhythmic "pacemaker" GABA activity on pyramidal neurons. The results of these experiments will discern developmental pathologic mechanisms of epileptogenesis associated with CD that cannot be obtained from animal CD models, and begin translational research studies that will provide insight into rational pharmacological treatments for pediatric CD patients with epilepsy.
描述(由申请人提供):切除性神经外科手术是治疗难治性癫痫儿童的常用治疗方法。大约一半的外科病例有皮质发育不良(CD),包括皮质分层异常、异位神经元、畸形巨细胞神经元和气球细胞。其他人有非CD病理,如梗死和Rasmussen综合征。本研究项目的目标是检查儿童CD组织细胞的电生理和解剖特性,以识别导致癫痫发生的机制。在上一个资助期,我们发现巨细胞神经元显示电压门控钙电流增加,巨细胞神经元和约30%的锥体神经元显示与未成熟皮质相似的Mg++敏感性NMDA受体减少。气球细胞没有显示积极的膜特性或突触活动。在初步研究中,我们还发现重症CD还有其他不成熟的特征。这些包括更多的GABA比谷氨酸自发突触电流和终端,更大的第1层诱发GABA介导的电流,GABA-A受体与去极化反转电位,更长的GABA-A受体衰减时间常数,和更多的interneurons比预期的,包括最近发现的巨细胞GABA神经元。这些发现使我们假设,严重的CD由一部分保留未成熟GABA信号传导特性的细胞组成,这些细胞与正常成熟样锥体细胞相互作用,产生“促癫痫”条件和癫痫发作。这一更新将通过确定严重CD中是否存在以下情况来解决这一假设:1)突触信号传导类似于具有GABA的未成熟皮质(2)巨细胞神经元和某些锥体神经元上的GABAA受体表现出不成熟的特征,如去极化反转电位;(3)GABA改变药物对GABA功能的增强具有兴奋性和“促癫痫”作用; 4)中间神经元表现出与锥体神经元上自发节律性“起搏点”GABA活性相关的不成熟特征。这些实验的结果将辨别与CD相关的癫痫发生的发育病理机制,这些机制不能从动物CD模型中获得,并开始转化研究,这些研究将为儿童CD癫痫患者提供合理的药物治疗。

项目成果

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GARY W. MATHERN其他文献

GARY W. MATHERN的其他文献

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{{ truncateString('GARY W. MATHERN', 18)}}的其他基金

Mechanisms Altering Electrical Conductivity & DTI in Epilepsy Surgery Patients
改变电导率的机制
  • 批准号:
    8013629
  • 财政年份:
    2010
  • 资助金额:
    $ 31.29万
  • 项目类别:
Mechanisms Altering Electrical Conductivity & DTI in Epilepsy Surgery Patients
改变电导率的机制
  • 批准号:
    7788906
  • 财政年份:
    2010
  • 资助金额:
    $ 31.29万
  • 项目类别:
Cortical Plasticity after Hemispherectomy
大脑半球切除术后的皮质可塑性
  • 批准号:
    7140373
  • 财政年份:
    2005
  • 资助金额:
    $ 31.29万
  • 项目类别:
Cortical Plasticity after Hemispherectomy
大脑半球切除术后的皮质可塑性
  • 批准号:
    6964960
  • 财政年份:
    2005
  • 资助金额:
    $ 31.29万
  • 项目类别:
PATHOPHYSIOLOGY OF DEVELOPING DYSPLASTIC HUMAN CORTEX
人类皮质发育不良的病理生理学
  • 批准号:
    6540132
  • 财政年份:
    1999
  • 资助金额:
    $ 31.29万
  • 项目类别:
PATHOPHYSIOLOGY OF DEVELOPING DYSPLASTIC HUMAN CORTEX
人类皮质发育不良的病理生理学
  • 批准号:
    6188291
  • 财政年份:
    1999
  • 资助金额:
    $ 31.29万
  • 项目类别:
PATHOPHYSIOLOGY OF DEVELOPING DYSPLASTIC HUMAN CORTEX
人类皮质发育不良的病理生理学
  • 批准号:
    2892731
  • 财政年份:
    1999
  • 资助金额:
    $ 31.29万
  • 项目类别:
Pathophysiology of Developing Dysplastic Human Cortex
人类皮质发育不良的病理生理学
  • 批准号:
    7534976
  • 财政年份:
    1999
  • 资助金额:
    $ 31.29万
  • 项目类别:
Pathophysiology of Developing Dysplastic Human Cortex
人类皮质发育不良的病理生理学
  • 批准号:
    7340399
  • 财政年份:
    1999
  • 资助金额:
    $ 31.29万
  • 项目类别:
Pathophysiology of Developing Dysplastic Human Cortex
人类皮质发育不良的病理生理学
  • 批准号:
    7848599
  • 财政年份:
    1999
  • 资助金额:
    $ 31.29万
  • 项目类别:

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