Mechanisms of cortical GABA interneuron differentiation

University Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): Several clinical observations suggest that GABAergic neurotransmission and GABAergic neurons in the cerebral cortex may be compromised in schizophrenic patients. Despite this evidence, it is not clear whether GABAergic dysfunction is a cause or a consequence of the disease process. Moreover, it is not known whether changes in GABAergic function reflect altered development of circuits to which GABAergic neurons contribute, or a degenerative process that follows normal differentiation. The UNC-CCNMD investigators have proposed the hypothesis that progressive changes in GABAergic systems accompany the development and onset of the disease, and that these changes reflect altered differentiation of GABAergic elements during adolescence and early adulthood. We will determine whether there are progressive or regressive changes in the dendritic and axonal arbors of cortical GABAergic interneurons during adolescence and early adulthood in mice to test this hypothesis at the level of the neural elements that constitute cortical GABAergic circuits. We will characterize dendritic and axonal differentiation in three molecularly distinct subclasses of GABAergic interneurons?those expressing calcium-binding proteins: calbindin, calretinin and parvalbumin. We will then determine whether signaling via the Rho family of GTPases mediates postnatal changes in GABAergic neurons. We will use this data on normal development as the basis of analysis of mice that carry mutations associated with schizophrenia vulnerability. These include haploinsufficiency of mouse homologues of human 22q11 genes, and mutations in the NCAM, BDNF and NT3 genes. These experiments will assist all of the center investigators in establishing a cellular substrate for changes in GABAergic function seen in patients who are at risk for schizophrenia or patients in the early stages of the disease (Projects 1 and 2). Also, it will establish potential cellular mechanisms for interpreting post-mortem studies that characterize changes in molecular markers for GABAergic neurons during adolescence and early adulthood (Project 3). Finally, our results will indicate the extent to which changes in GABAergic cortical circuit elements are the pathologic target of genes associated with schizophrenia vulnerability in schizophrenic patients.