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: 8279478
• 负责人: GEORGE BARD ERMENTROUT
• 金额: $ 25.58万
• 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/8279478
• 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研究了介导传播的功能性能和受体子类型 特定类别的GABA神经元在灵长类动物的局部电路中建立的抑制性突触连接 新皮层。研究的动机是由短期与持久的存在的假设 皮质网络中特定连接处的抑制性突触后电流（IPSC）可能会关联 具有高（伽玛，30-80Hz）和低（Theta，4-8 Hz）频率的某些内神经元子类的活性 振荡分别。具体而言，我们建议快速尖峰（FS）和非快速尖峰（NFS）神经元 通过快速和缓慢的IPSC发出信号。另外，我们假设离子旋转的不同亚型 GABA-A受体是FS和NFS神经元连接中的快速和慢速IPSC的基础。在 计算建模研究，我们将测试快速和缓慢的IPSC可能关联的想法的有效性 FS和NFS神经元带有γ和Theta网络振荡。体外电生理研究将 确定是否确实通过快速和慢速IPSC来确定FS和NFS神经元是否信号。另外，亚型 FS和NFS在连接上介导IPSC的GABA-A受体在 新皮质网络将使用在受体中起作用的新型苯二氮卓类化合物进行评估 亚型选择方式。这些研究将通过定量解剖学研究来支持 使用免疫细胞化学的GABA-A受体的亚型在不同类型的突触连接处 标记和荧光显微镜技术。在计算机模拟中获得的数据和 电生理研究将集成，以建立基于生物物理的新皮质模型 模拟了操纵受体亚型的影响的网络。鉴于先前的 描述了精神分裂症中GABA神经元和GABA-A受体亚型的改变，研究 项目2不仅会增加我们对疾病中的神经元功能和功能障碍的理解，而且还会增加 基于GABA-A受体的未来药理干预措施也可能具有预测价值 亚型。