Inhibition, Oscillations and Information Processing in Schizophrenia

描述（由申请人提供）：本中心的核心假设是，GABA神经元亚群中的一种独特的分子改变模式导致了精神分裂症信息处理缺陷的皮质网络振荡紊乱。皮层GABA神经传递标记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：parvalbumin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，这些神经元被认为分别在伽马（30-80 Hz）和θ (4-7 Hz)振荡的产生中发挥核心作用，这两种振荡在精神分裂症患者中都受到干扰。网络振荡至少在一定程度上取决于3个生理特性：1)GABA神经传递的强度[即抑制性突触后电流（IPSC）振幅]由突触前和突触后因素决定；2) GABA神经传递动力学（即IPSC持续时间）主要由突触后GABA- a受体的亚基组成决定；3) GABA-A受体被激活时氯离子流动所决定的抑制（即分流或超极化）的性质。这些生理特征依次依赖于特定基因产物的表达。因此，我们假设精神分裂症患者伽马和θ波振荡的改变反映了影响gaba介导抑制的强度、动力学或性质的基因产物的细胞类型特异性紊乱。在死后的人类大脑中，使用背外侧前额叶皮层（DLPFC）作为精神分裂症患者受影响的原型皮质区域，将进行研究，以确定1)精神分裂症患者GABA神经传递的突触前强度是否因PV和SST神经元中可用于合成GABA的GAD67蛋白的数量不足而受损；2) GABA- a受体a1和a2亚基表达的细胞类型特异性改变是否会破坏精神分裂症患者GABA神经传递动力学；3)精神分裂症中氯转运体表达的变化是否破坏了GABA神经元的分路抑制性输入和/或锥体细胞的超极化抑制性输入，这是稳健振荡所必需的。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拟议的研究并为其提供信息。因此，拟议研究的结果可能在精神分裂症振荡和信息处理缺陷的疾病机制以及确定治疗这些缺陷的新分子靶点方面提供了大量信息。

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.