'Partial' Rodent Model for GABA Defect in Schizophrenia

描述（由申请人提供）：越来越多的共识认为，包括前扣带回（ACG）和杏仁核在内的多个边缘区域参与精神分裂症的病理生理。这项研究的目的是使用一个“局部”啮齿动物模型，从一个复杂的皮质边缘电路网络中解剖出一个异常输入到其他边缘大脑区域的潜在来源，并使用细胞化学分析和行为测试来研究其影响。特别是，这些研究集中在精神分裂症中ACG异常可能反过来诱导杏仁核继发性变化的假设上。ACG和杏仁核相互关联，它们在精神分裂症病理生理中的作用正得到越来越多的支持。确凿的证据表明，在ACG中存在gaba能传输中断。在这些研究中，这种破坏将通过在年轻大鼠ACG中局部慢性输注GABAA受体拮抗剂来模拟药理学。将采用时间过程实验设计研究杏仁核诱导的神经化学变化。特别是，在1周、2周、4周的慢性、连续的、在4周治疗结束后3个月，在ACG中输注GABAA受体拮抗剂。然后，这些神经化学变化将与惊吓反应的测量相关联，以评估该模型在再现精神分裂症中描述的行为缺陷方面的有效性。这些方法的结合将协同工作，阐明不同神经回路内相互关联的变化及其对持久行为异常的影响。这些研究的意义在于，它们有可能提供在相互连接的大脑边缘区域检测到的精神分裂症神经化学异常之间的功能联系。

DESCRIPTION (provided by applicant): There is growing consensus that multiple limbic regions, including the anterior cingulate gyrus (ACG) and amygdala, are involved in the pathophysiology of schizophrenia. The aim of the proposed investigations is to use a 'partial' rodent model to dissect out, from a complex network of corticolimbic circuitry, one potential source of abnormal input to other limbic brain regions, and to investigate its effects using cytochemical assays and behavioral testing. In particular, these studies are focused on the hypothesis that, in schizophrenia, abnormalities in ACG may, in turn, induce secondary changes in amygdala. ACG and amygdala are massively interconnected and their role in the pathophysiology of schizophrenia is gaining growing support. Solid evidence indicates the presence in ACG of a disruption of GABAergic transmission. In these studies, such a disruption will be mimicked pharmacologically by local chronic infusion of a GABAA receptor antagonist in the ACG of young rats. Neurochemical changes induced in amygdala will be investigated using a time-course experimental design. In particular, densities of neurons expressing ionotropic glutamate receptors and glutamate amino decarboxylase (in situ hybridization and immunocytochemistry) and neuronal subpopulations expressing glutamate, GABA or the calcium binding proteins parvalbumin, calretinin or calbindin D28k (immunocytochemistry) will be measured in each amygdalar subdivision following 1, 2, 4 weeks of chronic, continuous, infusion of a GABAA receptor antagonist in ACG or 3 months after the end of a 4 weeks treatment. These neurochemical changes will be then correlated to measures of startle responsivity in order to assess the validity of this model in reproducing behavioral deficits described in schizophrenia. The combination of these methods will work synergistically to shed light on inter-related changes within distinct neural circuitry and their effect on lasting behavioral abnormalities. The significance of these studies resides in their potential of providing functional links between neurochemical abnormalities in schizophrenia detected in interconnected limbic brain regions.