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

全基因组连锁研究、病例对照关联研究和功能数据表明， 神经调节蛋白1(NRG1)与精神分裂症病因学的关系发育研究表明，NRG1中的缺陷 通过其受体ErbB4介导的信号转导可能导致错误的产生、放置、 发育中大脑中神经元的分化和功能(Corfas等人，2004年)。由此产生的变化 因此，大脑皮层的神经回路可能会导致神经发育障碍，如精神分裂症。 最近的证据表明，改变的NRG1-ERBB4相互作用可能会增强对 精神分裂症(Norton等人，2005；Hahn等人，2006)以及NRG1(I)表达在 精神分裂症患者的背外侧前额叶皮质和海马体(Hashimoto et al 2004；Law et al.，2006) 进一步支持这一假设。因此，对NRG1和ERBB4受体功能的理解 在发育中的大脑皮层，特别是在神经元间发育期间，对于描绘 神经发育通路的中断可能与糖尿病的发展密切相关 精神分裂症。我们建议通过研究以下三个相关问题来实现这一目标： 确定胚胎大脑皮层中间神经元的迁移和定位模式，(2) 确定在早期胚胎发育过程中，中间神经元的发育和分化 出生后，取决于NRG1-ErbB4的相互作用，以及(3)确定ErbB4在功能中的作用 大脑皮层中间神经元。 。

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. .