Project 1: The Molecular Basis For Alterations in GABA-Mediated network Oscillati

项目 1：GABA 介导的网络振荡改变的分子基础

• 批准号: 8105261
• 负责人: David A Lewis
• 金额: $ 100.05万
• 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/8105261
• 关键词: Accounting; Action Potentials; Address; Affect; Alcohol or Other Drugs use; Alcohols; Autopsy; Brain; Cells; Chloride Ion; Chlorides; Confocal Microscopy; Disease; Exhibits; Frequencies; GABA-A Receptor; Generations; Glutamate Decarboxylase; Human; In Situ Hybridization; Investigation; Kinetics; Label; Link; Mediating; Membrane Potentials; Messenger RNA; Methods; Modeling; Molecular; Molecular Target; Nature; Neurons; Nicotine; Outcome; Parvalbumins; Pattern; Pharmaceutical Preparations; Physiological; Play; Population; Prefrontal Cortex; Presynaptic Terminals; Process; Property; Proteins; Pyramidal Cells; Relative (related person); Rest; Role; Schizophrenia; Somatostatin; Study Subject; Synapses; Testing; Time; Tissues; Transcript; Western Blotting; base; cell type; gamma-Aminobutyric Acid; human subject; immunoreactivity; information processing; innovation; mRNA Expression; neurotransmission; nonhuman primate; novel; presynaptic; receptor; research study; suicidal morbidity; symporter; uptake; vesicular GABA transporter

The central hypothesis of this Center posits that a distinctive pattern of molecular alterations in subsets of GABA neurons gives rise to disturbances in cortical network oscillations that underlie the information processing deficits of schizophrenia. Disturbances in markers of cortical GABA neurotransmission are common in schizophrenia and are most prominent in two types of GABA neurons: parvalbumin-positive (PV), fast-spiking neurons and somatostatin-positive (SST), low-threshold spiking neurons. PV and SST cells each form networks with neurons of the same type that are thought to play central roles in the generation of gamma (30-80 Hz) and theta (4-7 Hz) oscillations, respectively, both of which are disturbed in subjects with schizophrenia. Network oscillations depend, at least in part, on 3 physiological properties: 1) the strength [i.e., inhibitory post-synaptic current (IPSC) amplitude] of GABA neurotransmission as determined by both pre- and post-synaptic factors; 2) the kinetics (i.e., IPSC duration) of GABA neurotransmission as determined principally by the subunit composition of post-synaptic GABA-A receptors; and 3) the nature of the resulting inhibition (i.e., shunting or hyperpolarizing) as determined by chloride ion flow when GABA-A receptors are activated. Each of these physiological features is, in turn, dependent upon the expression of particular sets of gene products. Consequently, we hypothesize that the alterations in gamma and theta oscillations in schizophrenia reflect cell type-specific disturbances in the gene products that influence the strength, kinetics or nature of GABA-mediated inhibition. Studies in postmortem human brain, using the dorsolateral prefrontal cortex (DLPFC) as a prototypic cortical region affected in schizophrenia, will be conducted to determine if 1) the presynaptic strength of GABA neurotransmission in schizophrenia is impaired due to deficits in the amount of GAD67 protein available to synthesize GABA in PV and SST neurons; 2) if cell type-specific alterations in the expression of a1 and a2 GABA-A receptor subunits disrupt the kinetics of GABA neurotransmission in schizophrenia; and 3) if shifts in the expression of chloride transporters in schizophrenia disrupt the shunting inhibitory input to GABA neurons and/or the hyperpolarizing inhibitory input to pyramidal cells required for robust oscillations. The proposed studies are both methodologically and conceptually innovative, and these investigations depend upon and inform the studies proposed in other projects in this Center. Thus, the outcomes of the proposed studies are likely to be highly informative regarding both the disease mechanisms underlying oscillatory and information processing deficits in schizophrenia and in identifying novel molecular targets for treating these deficits.

该中心的核心假设假定，在细胞亚群中， GABA神经元引起的干扰皮层网络振荡的基础信息 精神分裂症的处理缺陷皮质GABA神经传递标志物的紊乱是 常见于精神分裂症中，并且在两种类型的GABA神经元中最突出：小清蛋白阳性（PV）， 快速发放神经元和生长抑素阳性（SST）低阈值发放神经元。PV和SST电池各 与被认为在产生神经元中起核心作用的相同类型的神经元形成网络。 γ（30-80 Hz）和θ（4-7 Hz）振荡，这两种振荡在患有 精神分裂症网络振荡至少部分取决于3个生理特性：1）强度 [i.e.,抑制性突触后电流（IPSC）振幅]的GABA神经传递，由两个 突触前和突触后因子; 2）动力学（即，IPSC持续时间）的GABA神经传递， 主要由突触后GABA-A受体的亚基组成决定;和3） 得到的抑制（即，当GABA-A 受体被激活。这些生理特征中的每一个反过来又取决于 特定的基因产物。因此，我们假设伽马和θ的改变 精神分裂症中的振荡反映了基因产物中细胞类型特异性的干扰， GABA介导的抑制的强度、动力学或性质。在死后人脑的研究中，使用 背外侧前额叶皮层（DLPFC）作为精神分裂症中受影响的原型皮层区域，将被 进行以确定1）精神分裂症中GABA神经传递的突触前强度是否 由于PV和SST中可用于合成GABA的GAD 67蛋白量不足而受损 2）如果细胞类型特异性改变α 1和α 2 GABA-A受体亚单位的表达， 精神分裂症中GABA神经传递的动力学;以及3）如果氯的表达发生变化， 精神分裂症中的转运蛋白破坏了对GABA神经元的分流抑制性输入和/或 对锥体细胞的超极化抑制性输入是产生强振荡所必需的。拟议的研究是 无论是方法上和概念上的创新，这些调查依赖于并告知 本中心其他项目中提出的研究。因此，拟议研究的结果可能是 关于振荡和信息处理的疾病机制的高度信息 精神分裂症的缺陷和识别治疗这些缺陷的新分子靶点。