'Partial' Rodent Model for GABA Defect in Schizophrenia

点击翻译按钮获取中文摘要

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.