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: 8376055
• 负责人: GEORGE BARD ERMENTROUT
• 金额: $ 25.89万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8376055
• 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; information processing; 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研究介导信息传递的功能特性和受体亚型 特定类型GABA神经元在灵长类动物局部环路中的抑制性突触联系 大脑皮层。这些研究的动机是假设短期与长期的存在 皮层网络中特定连接的抑制性突触后电流(IPSCs)可能与 高(伽马，30-80赫兹)和低(4-8赫兹)频率的某些中间神经元亚类的活动 分别是振荡。具体地说，我们认为快峰电位(FS)和非快峰电位(NFS)神经元 分别通过快速和慢速iPSC发送信号。此外，我们假设不同的离子亲和性亚型 GABA-A受体构成了来自FS和NFS神经元连接的快慢IPSCs的基础。在……里面 在计算建模研究中，我们将测试快和慢ipscs可能关联的想法的有效性 具有Gamma和theta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的IPSCs发出信号。此外，的子类型 GABA-A受体在FS和NFS建立的连接中介导IPSCs到其他细胞的连接 将使用作用于受体的新型苯二氮卓类化合物来评估新皮质网络 亚型选择方式。这些研究将得到定量解剖学研究的支持 不同类型突触连接中GABA-A受体亚型的免疫细胞化学研究 标记和荧光显微镜技术。在计算机模拟中获得的数据和 将整合电生理学研究，以建立基于生物物理学的新皮质模型 模拟操纵受体亚型的效果的网络。根据以前的情况 描述了精神分裂症患者GABA神经元和GABA-A受体亚型的变化， 项目2不仅将增加我们对疾病中神经元间功能和功能障碍的了解，而且 在以GABA-A受体为基础的未来药物干预方面也可能具有预测价值 子类型。