Epileptogenesis in a rat model of cortical malformation

皮质畸形大鼠模型的癫痫发生

• 批准号: 6835757
• 负责人: Stacey A Trotter
• 金额: $ 2.8万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6835757
• 关键词: GABA receptor; SDS polyacrylamide gel electrophoresis; cerebral cortex; confocal scanning microscopy; epilepsy; fluorescence microscopy; genetic disorder; genetic models; immunocytochemistry; laboratory rat; neocortex; neurotransmitter transport; predoctoral investigator; voltage /patch clamp; western blottings

DESCRIPTION (provided by applicant): Cortical malformations are commonly associated with medically-intractable epilepsies. A clear understanding of the role of such malformations in aberrant neural activity could provide insights for the treatment of these poorly managed disorders. This proposal will use a genetic animal model of a human cortical malformation, subcortical band heterotopia (SBH; or double cortex), in which large bilateral heterotopia are associated with spontaneous recurrent seizures. The rat model, termed "tish", provides unique opportunities for investigating both the development of malformations and mechanisms of epilepsy. Preliminary electrophysiological studies indicate that inhibitory GABAergic synaptic transmission is disturbed in the tish rat neocortex. Based on these observations, we hypothesize that altered inhibitory synaptic activity in the tish cortex predisposes the brain to seizures. Specific Aim 1 will characterize GABAergic synaptic inhibition in the tish rat neocortex using whole-cell patch clamp recording techniques in acute brain slices of the tish neocortex. It is important to note that GABAA receptors (GABAAR) undergo maturational changes in subunit composition during cortical development, and it is possible that this normal developmental process is disturbed in the tish cortex. Experiments will therefore be undertaken at multiple developmental time points during which key changes in GABAAR composition and function are known to occur. Specific Aim 2 will identify alterations in GABAAR subunits/subtypes, and GABA transporters in the developing and adult tish neocortex. Changes in these molecular substrates can affect the functional characteristics of GABAergic transmission, and any observed changes will be compared with the electrophysiological features defined in Aim 1. Together, these studies will elucidate fundamental features of a key inhibitory system in a dysplastic, seizure-prone brain.

描述（由申请人提供）： 皮质畸形通常与医学上的癫痫发作有关。对这种畸形在异常神经活动中的作用的清晰了解可以为治疗这些管理不善的疾病提供见解。该提案将使用人皮质畸形，皮质带异位症（SBH；或双皮层）的遗传动物模型，其中大双侧异位症与自发性复发性癫痫发作有关。称为“ Tish”的大鼠模型为研究畸形和癫痫机制的发展提供了独特的机会。初步电生理研究表明，抑制性GABA能突触传播在Tish大鼠新皮层中受到干扰。基于这些观察结果，我们假设改变了Tish皮质中的抑制性突触活性使大脑遭受癫痫发作。特定的目标1将使用全细胞贴片夹夹技术在Tish Neofortex的急性脑切片中使用全细胞贴片夹技术来表征Tish大鼠新皮层中的GABA能突触抑制作用。重要的是要注意，Gabaa受体（GABAAR）在皮质发育过程中经历了亚基组成的成熟变化，并且这种正常发育过程可能会在Tish Cortex中受到干扰。因此，将在多个发育时间点进行实验，在此过程中，已知Gabaar组成和功能的关键变化发生。具体的目标2将确定加巴亚基/亚型的变化以及发展中和成人新皮层中的GABA转运蛋白。这些分子底物的变化会影响GABA能传播的功能特征，并且将观察到的任何变化与AIM 1中定义的电生理特征进行比较。共同，这些研究将阐明在发育不良，癫痫发作，癫痫发作的大脑中关键抑制系统的基本特征。