'Partial' Rodent Model for GABA Defect in Schizophrenia

描述(申请人提供)：越来越多的人达成共识，认为多个边缘区域，包括前扣带回(ACG)和杏仁核，参与了精神分裂症的病理生理学。这项拟议中的研究的目的是利用一个部分的啮齿动物模型，从皮质边缘回路的复杂网络中分离出一个潜在的异常输入来源，并使用细胞化学分析和行为测试来研究其影响。特别是，这些研究集中在这样一个假设上，即在精神分裂症患者中，ACG的异常反过来可能会导致杏仁核的继发性变化。ACG和杏仁核是相互联系的，它们在精神分裂症的病理生理学中的作用得到了越来越多的支持。确凿的证据表明，ACG中存在GABA能传递的中断。在这些研究中，这种干扰将通过在幼年大鼠的ACG中局部慢性注入GABAA受体拮抗剂来模拟。将使用时程实验设计来研究杏仁核中诱导的神经化学变化。特别是，在ACG内长期、连续、持续注射GABAA受体拮抗剂1周、2周、4周后，或在4周治疗结束后3个月，将测量杏仁核每个亚区表达离子型谷氨酸受体和谷氨酸氨基脱羧酶的神经元(原位杂交和免疫细胞化学)和表达谷氨酸、GABA或钙结合蛋白小白蛋白、钙结合蛋白D28k的神经元亚群(免疫细胞化学)。然后，将这些神经化学变化与惊吓反应的测量相关联，以评估该模型在复制精神分裂症所描述的行为缺陷方面的有效性。这些方法的结合将协同作用，阐明不同神经回路中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，它们有可能在精神分裂症的神经化学异常之间提供功能联系，这些异常是在相互连接的边缘脑区域检测到的。

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.