Expression and function of disrupted-in-schizophrenia 1 in the developing mouse hippocampus.

摘要

Schizophrenia is a severely debilitating psychiatric disorder which affects approximately 1% of the population worldwide. Although the precise etiology of schizophrenia is unknown, research to date suggests that the disease is a neurodevelopmental disorder caused by a combination of adverse genetic and environmental factors. Several risk genes have been identified thus far, one of the most promising candidates being the Disrupted-In-Schizophrenia 1 (DISC1) gene. In an effort to better understand how genetic alterations in DISC1 may contribute to disease susceptibility, we sought to determine the role that DISC1 plays in the development of the hippocampus, an area which shows consistent abnormalities in the schizophrenic brain.The first goal of our investigation was to determine where DISC1 is expressed in the developing hippocampus and how this expression pattern might change with hippocampal maturation. Using two commercially available antibodies, we analyzed the expression pattern of Disc1 in the developing mouse hippocampus at various ages from late embryogenesis to adulthood. Our analysis revealed that at late embryonic and early postnatal ages, when the hippocampus is still developing, Disc1 is expressed prominently throughout the hippocampus. In addition, Disc1 is strongly expressed in the stream of granule cells migrating toward the future dentate gyrus. As the hippocampus matures, Disc1 expression becomes more specified to the pyramidal cells of CA1-CA3 and the granule cells of the dentate gyrus. This expression pattern continues into adulthood, with a slight reduction in the level of Disc1 expression in CA1 pyramidal cells at later ages.Given our finding that Disc1 is expressed by the cells of the dentate migratory stream, and since Disc1 is known to regulate neuronal migration in the developing cerebral cortex, we wondered whether Disc1 plays a role in granule cell migration in the developing hippocampus. To investigate this question, we used in utero electroporation to deliver Disc1 shRNAs into the developing hippocampus. We discovered that Disc1 loss of function inhibits granule cell migration, a phenotype that could be rescued by overexpression of human DISC1. Moreover, we found that the degree to which Disc1 levels are reduced influences the degree to which granule cell migration is inhibited, suggesting that the amount of Disc1 available in these cells is important for proper granule cell migration.In order to understand how DISC1 abnormalities contribute to an increased risk for developing schizophrenia, it is important to determine the neurobiological pathways through which DISC1 acts. Our findings support a role for DISC1 in hippocampal development, in particular in the regulation of granule cell migration. Since the granule cells of the dentate gyrus relay signals between cortical afferents and the rest of the hippocampus, the proper positioning and connectivity of these cells is necessary for normal hippocampal function. Thus, DISC1 mutations which compromise its ability to properly regulate granule cell migration could lead to abnormal hippocampal development and function. Such abnormalities could in turn cause a more favorable environment for the onset of schizophrenia later in life.