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.

该中心的中心假设认为，在 GABA神经元引起了皮质网络振荡的干扰，这些振荡是信息的基础 精神分裂症的处理缺陷。皮质GABA神经传递标记中的干扰是 在精神分裂症中常见，在两种类型的GABA神经元中最突出：白蛋白阳性（PV）， 快速刺激的神经元和生长抑素阳性（SST），低阈值尖峰神经元。 PV和SST细胞每个 形成具有相同类型的神经元的网络，这些神经元被认为在一代中起着核心作用 伽马（30-80 Hz）和theta（4-7 Hz）振荡，两者在患有受试者的受试者中受到干扰 精神分裂症。网络振荡至少部分取决于3种生理特性：1）强度 [即抑制性突触后电流（IPSC）振幅] GABA神经传递。 前后突触后因素； 2）GABA神经传递的动力学（即IPSC持续时间） 主要是通过突触后GABA-A受体的亚基组成确定的； 3） 当GABA-A时，由氯离子流确定所得的抑制作用（即分流或超极化） 受体被激活。这些生理特征中的每一个又取决于 特定的基因产品集。因此，我们假设伽马和theta的改变 精神分裂症的振荡反映了影响影响的基因产物中细胞类型的障碍 GABA介导的抑制的强度，动力学或性质。使用尸体后人脑的研究 背外侧前额叶皮层（DLPFC）作为在精神分裂症中受影响的原型皮质区域 进行确定1）精神分裂症中GABA神经传递的突触前强度是 由于可用于合成PV和SST合成GABA的GAD67蛋白质的缺陷而受损 神经元； 2）如果A1和A2 GABA-A受体亚基的表达中特定于细胞类型的变化破坏 精神分裂症中GABA神经传递的动力学； 3）如果氯化物的表达移动 精神分裂症中的转运蛋白破坏了对GABA神经元和/或 对稳健振荡所需的锥体细胞的超极化抑制作用。拟议的研究是 从方法论和概念上都是创新的，这些调查都取决于并告知 该中心其他项目提出的研究。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 精神分裂症的缺陷以及确定治疗这些缺陷的新分子靶标。