COBRE: UND: ADRENERGIC MODULATION OF SEIZURES & NEURODEGENERATION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。这项研究的广泛，长期目标是找到一种更好的治疗策略，用于预防与复发性不受控制的癫痫发作或癫痫相关的神经变性（神经元损伤和细胞死亡）。该项目的直接目标是表征α 1肾上腺素能受体（α 1AR）激活对中间神经元的影响。目前使用的许多抗癫痫药物增强γ-氨基丁酸（GABA）介导的抑制。GABA是大脑中主要的抑制性神经递质，其主要来源是一小群被称为中间神经元的抑制性细胞。许多传统的抗癫痫药物不靶向中间神经元，而是在GABAA受体水平上增强GABA的作用。几种新的、更有效的第二代抗癫痫药物似乎通过增加GABA的量来起作用，或者通过增强其合成，或者通过抑制其催化或再摄取。然而，这些药物都没有直接激活中间神经元。几条证据表明，α 1 AR激活具有强效抗癫痫作用。这种效应的机制尚不清楚。初步研究表明，α AR激活兴奋中间神经元的亚群，导致增强的GABA释放。这一发现可能是非常重要的，我们假设，选择性α 1 AR激活抑制性GABA能中间神经元可能提供一种新的治疗策略，用于预防癫痫发作和神经退行性变。本研究将检验这一假设。本研究采用电生理学、分子生物学和神经影像学相结合的跨学科研究方法，旨在：1）研究α 1 AR激活对中间神经元的影响; 2）鉴定α 1 AR介导这些反应的特定亚型; 3）确定α 1 AR激活的中间神经元的连接、神经化学和突触学特征;和4）检查α 1 AR激活对神经元兴奋性的功能后果。从这项研究中获得的信息不仅将对中间神经元的解剖学，生理学和药理学产生重要的见解，而且还可能导致一类新的抗癫痫药物的开发，这些药物具有改善的神经保护作用和增强的治疗癫痫的疗效。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The broad, long-term objective of this research is to find a better therapeutic strategy for preventing neurodegeneration (neuronal damage and cell death) associated with recurring uncontrolled seizures or epilepsy. The immediate goal of this project is to characterize the effects of alpha-1 adrenergic receptor (alpha1AR) activation on interneurons. Many of the currently employed antiepileptic drugs enhance gamma-aminobutyric acid (GABA)-mediated inhibition. The major source of GABA, the predominant inhibitory neurotransmitter in the brain, is a small population of inhibitory cells known as interneurons. Many of the traditional antiepileptic drugs do not target interneurons, but rather potentiate actions of GABA at the level of the GABAA receptor. Several of the new, more effective second generation antiepileptic drugs appear to act by increasing the amount of GABA available, either by enhancing its synthesis or by inhibiting its catabolism or reuptake. However, none of these drugs directly activate interneurons. Several lines of evidence indicate that alpha1AR activation is potently antiepileptogenic. The mechanism underlying this effect is unknown. Preliminary studies suggest that alphaAR activation excites a subpopulation of interneurons leading to enhanced GABA release. This finding may be very important and we hypothesize that selective alpha1AR activation of inhibitory GABAergic interneurons may provide a novel therapeutic strategy for the prophylaxis of seizures and neurodegeneration. This study will test this hypothesis. Using a cross-disciplinary approach combining electrophysiological, molecular biological, and neuroimaging techniques, we will address the following specific aims: 1) characterize the effects of alpha1AR activation on discrete populations of interneurons; 2) identify the particular subtype of alpha1AR mediating these responses; 3) ascertain the connectivity, neurochemistry and synaptological profile of alpha1AR-activated interneurons; and 4) examine the functional consequences of alpha1AR activation on neuronal excitability. The information derived from this research not only will yield important insights into the anatomy, physiology and pharmacology of interneurons, but also may lead to the development of a new class of antiepileptic drugs with improved neuroprotective actions and enhanced efficacy for treating epilepsy.