Project 2: Functional Role of GABA Recaptor Subunit-Specific Transmission in Neoc

项目 2：GABA 受体亚基特异性传输在 Neoc 中的功能作用

• 批准号: 8105262
• 负责人: GEORGE BARD ERMENTROUT
• 金额: $ 14.11万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105262
• 关键词: Benzodiazepines; Cells; Computer Simulation; Coupling; Data; Fluorescence Microscopy; Frequencies; Functional disorder; Future; GABA-A Receptor; In Vitro; Interneuron function; Interneurons; Intervention; Investigation; Kinetics; Label; Light; Macaca; Mediating; Modeling; Monkeys; Neocortex; Neurons; Predictive Value; Presynaptic Terminals; Primates; Production; Property; Protein Subunits; Pyramidal Cells; Role; Schizophrenia; Signal Transduction; Simulate; Slice; Synapses; Techniques; Testing; base; gamma-Aminobutyric Acid; neocortical; novel; postsynaptic; receptor; transmission process

Project 2-Ermentrout investigates the functional properties and receptor subtypes mediating transmission at the inhibitory synaptic connections made by specific classes of GABA neurons in local circuits of the primate neocortex. The studies are motivated by the hypothesis that the presence of short- versus long-lasting inhibitory postsynaptic currents (IPSCs) at specific connections in the cortical network may associate the activity of certain interneuron subclasses with high (gamma, 30-80Hz) and low (theta, 4-8 Hz) frequency oscillations, respectively. Specifically, we suggest that fast spiking (FS) and non-fast-spiking (nFS) neurons signal via fast and slow IPSCs, respectively. In addition, we hypothesize that different subtypes of ionotropic GABA-A receptors underlie the fast and slow IPSCs in connections from FS and nFS neurons. In computational modeling studies, we will test the validity of the idea that fast and slow IPSCs may associate FS and nFS neurons with gamma and theta network oscillations. Electrophysiological studies in vitro will determine whether indeed FS and nFS neurons signal via fast and slow IPSCs. In addition, the subtypes of GABA-A receptors mediating the IPSCs at connections made by FS and nFS onto other cells of the neocortical network will be assessed using novel benzodiazepine-like compounds that act in a receptor subtype-selective manner. These investigations will be supported by quantitative anatomical studies of the subtype of GABA-A receptor at the different types of synaptic connections using immunocytochemical labeling and fluorescence microscopy techniques. The data obtained in the computer simulations and electrophysiological studies will be integrated in order to build a biophysically-based model of the neocortical network in which the effects of manipulating receptor subtypes is simulated. In light of the previously described alterations in GABA neurons and GABA-A receptor subtypes in schizophrenia, the studies in Project 2 will not only increase our understanding of interneuron function and dysfunction in the illness, but may also have predictive value in terms of future pharmacological interventions based on GABA-A receptor subtypes.

项目2-Ermentrout研究了介导传输的功能特性和受体亚型， 在灵长类动物的局部回路中由特定类别的GABA神经元形成的抑制性突触连接 新皮层这些研究的动机是这样一个假设，即短期与长期的存在 皮层网络中特定连接处的抑制性突触后电流（IPSC）可能与 具有高（γ，30- 80 Hz）和低（θ，4- 8Hz）频率的某些中间神经元亚类的活动 振荡，分别。具体来说，我们认为，快速发放（FS）和非快速发放（nFS）神经元， 分别通过快速和慢速IPSC发信号。此外，我们假设不同亚型的离子型 GABA-A受体是FS和nFS神经元连接中快和慢IPSC的基础。在 通过计算模型研究，我们将测试快速和慢速IPSC可能与 具有伽马和θ网络振荡的FS和nFS神经元。体外电生理学研究将 确定FS和nFS神经元是否确实通过快和慢IPSC发出信号。此外， GABA-A受体介导FS和nFS连接到其他细胞的IPSC。 新皮质网络将使用新型苯二氮卓类化合物进行评估， 子类型选择性方式。这些调查将得到定量解剖学研究的支持， GABA-A受体亚型在不同类型的突触连接，使用免疫细胞化学 标记和荧光显微镜技术。在计算机模拟中获得的数据和 电生理学研究将被整合，以建立一个基于生物药理学的新皮层模型， 网络，其中操纵受体亚型的影响被模拟。鉴于此前 描述了精神分裂症中GABA神经元和GABA-A受体亚型的改变， 项目2不仅将增加我们对疾病中中间神经元功能和功能障碍的理解， 在未来基于GABA-A受体的药物干预方面也可能具有预测价值 亚型