Inhibition, Oscillations and Information Processing in Schizophrenia

精神分裂症的抑制、振荡和信息处理

• 批准号: 7667212
• 负责人: David A Lewis
• 金额: $ 212.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667212
• 关键词: Inhibition; Oscillations; Information; Processing; Schizophrenia

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：该中心的中心假设是，GABA神经元亚群中分子改变的独特模式引起皮质网络振荡的干扰，这是精神分裂症信息处理缺陷的基础。皮质GABA神经传递标志物的紊乱在精神分裂症中很常见，并且在两种类型的GABA神经元中最为突出：小白蛋白阳性（PV）、快速尖峰神经元和生长抑素阳性（SST）、低阈值尖峰神经元。PV和SST细胞各自与相同类型的神经元形成网络，所述神经元被认为分别在γ（30-80 Hz）和θ（4-7 Hz）振荡的产生中发挥中心作用，这两者在精神分裂症受试者中都受到干扰。网络振荡至少部分取决于3个生理特性：1）强度[即，GABA神经传递的抑制性突触后电流（IPSC）幅度]; 2）动力学（即，IPSC持续时间），如主要由突触后GABA-A受体的亚基组成确定的;和3）所产生的抑制的性质（即，分流或超极化），这是当GABA-A受体被激活时通过氯离子流确定的。这些生理特征中的每一个又取决于特定基因产物组的表达。因此，我们假设，在伽马和θ振荡精神分裂症的变化反映了细胞类型特异性干扰的基因产物，影响GABA介导的抑制的强度，动力学或性质。将对死后人脑进行研究，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，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神经元中可用于合成GABA的GAD 67蛋白量的不足而受损;（2）在精神分裂症中，α 1和α 2 GABA-A受体亚单位表达的细胞类型特异性改变是否破坏了GABA神经传递的动力学;和3）如果精神分裂症中氯转运蛋白表达的变化破坏了对GABA神经元的分流抑制输入，和/或或者是对锥体细胞的超极化抑制性输入，这是强大振荡所必需的。拟议的研究在方法和概念上都是创新的，这些调查依赖于本中心其他项目中提出的研究并为之提供信息。因此，拟议的研究结果可能是高度信息化的振荡和信息处理缺陷的精神分裂症的疾病机制，并在确定新的分子靶点治疗这些缺陷。