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

该中心的中心假设是，在亚群中存在一种独特的分子变化模式。 GABA神经元在作为信息基础的皮质网络振荡中引起干扰 精神分裂症的处理缺陷。皮质GABA神经传递标记物的紊乱 在精神分裂症中常见，在两种类型的GABA神经元中最为突出：小白蛋白阳性(PV)， 快速放电神经元和生长抑素阳性(SST)、低阈值放电神经元。光伏电池和海温电池 与相同类型的神经元形成网络，这些神经元被认为在产生 分别是伽马(30-80赫兹)和西塔(4-7赫兹)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 由两者决定的GABA神经传递的[即抑制突触后电流(IPSC)幅度] 突触前和突触后因子；2)GABA神经传递的动力学(即IPSC时程) 主要由突触后GABA-A受体的亚单位组成决定；以及3) 由此产生的抑制(即，分流或超极化)，由氯离子流动确定当GABA-A 感受器被激活。这些生理特征中的每一个反过来又依赖于 特定的几套基因产品。因此，我们假设伽马和西塔的变化 精神分裂症患者的振荡反映了基因产物中影响细胞类型的特定障碍 GABA介导的抑制的强度、动力学或性质。在死后人脑中的研究，使用 背外侧前额叶皮质(DLPFC)作为精神分裂症患者的典型皮质区域，将被 以确定1)精神分裂症患者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GAD67蛋白数量不足而受损 神经元；2)如果a1和a2 GABA-A受体亚单位表达的细胞类型特异性改变破坏 精神分裂症患者GABA神经传递的动力学；3)氯的表达发生变化 精神分裂症患者的转运蛋白干扰分流抑制传入GABA神经元和/或 强健振荡所需的锥体细胞超极化抑制输入。建议进行的研究包括 在方法和概念上都是创新的，这些调查依赖于并告知 在该中心的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都有很高的信息量 精神分裂症的缺陷和确定治疗这些缺陷的新的分子靶点。

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.