Project 5-Neuregulin 1-Erb4 Interactions in Cortical Interneuron Development

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Genome wide linkage studies, case-control association studies, and functional data suggest a role for Neuregulin 1 (NRG1) in the e'tiology of schizophrenia. Developmental studies indicate that defects in NRG1 signaling mediated through its receptor, ErbB4, could lead to the incorrect generation, placement, differentiation, and function of neurons in the developing brain (Corfas et al., 2004). The resultant changes in neural circuitry in the cerebral cortex may thus lead to neurodevelopmental disorder such as schizophrenia. Recent evidence indicating that altered NRG1-erbB4 interactions may enhance susceptibility to Schizophrenia (Norton et al.,2005; Hahn et al.,2006) and that NRG1(I) expression is deregulated in dorsolateral prefrontal cortex and hippocampus in schizophrenia (Hashimoto et al 2004; Law et al., 2006) further support this hypothesis. Therefore, an understanding of the functions of NRG1 and erbB4 receptors in the developing cerebral cortex, especially during interneuronal development, is essential to delineate the neurodevelopmental pathways whose disruption is likely to be integrally related to the development of schizophrenia. We propose to accomplish this by examining the following three related questions: (i) Determine the patterns of migration and positioning of interneurons in the embryonic cerebral cortex, (2) Determine whether the development and differentiation of interneurons, during early embryonic development and postnatally, depends on NRG1- ErbB4 interactions, and (3) Determine the role of ErbB4 in the function of cortical interneurons. .