NRG1-ErbB4 regulation of synaptic plasticity and behavior

精神分裂症（SZ）是一种致残性精神障碍，影响全球约1%的人口，是美国第七大最昂贵的疾病。它会改变大脑感知、情感和判断的基本过程，从而导致幻觉、妄想、思维障碍、快感缺乏和认知缺陷。与阿尔茨海默病和帕金森病等神经退行性疾病不同，SZ缺乏病理特征，因此仍然是最不为人所知的脑部疾病之一。SZ被认为是一种神经发育障碍，由神经发育过程中的问题导致青少年和成人的神经传递和可塑性受损。虽然牵涉到谷氨酸能和氨基丁酸能途径的功能低下，但潜在的分子机制尚不清楚。近年来对SZ易感基因的鉴定及其功能的研究已经开始揭示其病理生理。根据相关研究，生长因子神经调节蛋白1 （NRG1）及其受体ErbB4在不同人群中都是SZ的危险基因。这一观点得到了近期meta分析、全基因组关联研究和全基因组拷贝数分析的支持。与SZ的神经发育假说一致，NRG1和ErbB4参与了神经发育的各个步骤。特别是，ErbB4在中间神经元中特异性表达，体外和体内研究表明，ErbB4在gaba能回路的组装中起着关键作用。另一方面，NRG1和ErbB4在成人大脑中表达；NRG1急性治疗可增加皮质和海马中GABA的释放。阻断NRG1/ErbB4信号通路可减少GABA的释放，增加锥体神经元的放电，增强长期增强（LTP）。ErbB4突变小鼠表现出sz相关的行为缺陷，包括PPI和工作记忆受损。虽然这些观察结果令人兴奋，但也提出了几个关键问题。尽管已知NRG1和ErbB4促进GABA能传递，但我们对它们在大脑中的功能的理解存在一个明显的差距，即NRG1如何刺激中间神经元释放GABA的确切机制知之甚少。在成年ErbB4突变小鼠中观察到的行为缺陷是由于神经发育异常，还是成年期突触功能障碍，还是两者兼而有之？成人ErbB4表达能减轻行为缺陷和突触功能障碍吗？为了解决这些问题，我们1)研究NRG1促进GABA释放的机制；2)确定ErbB4突变导致突触功能障碍和行为缺陷的关键时间窗；3)通过急性抑制研究ErbB4激酶活性在突触功能和行为中的作用。结果将提供原则性证据，证明相关SZ可能通过恢复或恢复ErbB4的表达或活性来治疗。这些信息可能对研究其他SZ易感基因和开发新的治疗策略有用。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a disabling mental disorder that affects ~ 1 % of the population worldwide and the seventh most costly illness in USA. It alters basic brain processes of perception, emotion, and judgment to cause hallucinations, delusions, thought disorder, anhedonia and cognitive deficits. Unlike neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, SZ lacks pathological hallmarks and thus remains one of the least understood brain disorders. SZ is considered a neurodevelopmental disorder, resulting from problems during neural development that lead to impaired neurotransmission and plasticity in adolescent and adult. Although hypofunction of glutamatergic and GABAergic pathways have been implicated, underlying molecular mechanisms are poorly understood. Recent identification of SZ susceptibility genes and studies of their functions have begun to shed light on its pathophysiology. Both neuregulin 1 (NRG1), a growth factor, and its receptor ErbB4 are SZ risk genes in diverse populations based on association studies. This notion is supported by recent meta-analysis, genome-wide association study, and genome-wide copy number analysis. Consistent with the neurodevelopmental hypothesis for SZ, NRG1 and ErbB4 have been implicated in various steps of neural development. In particular, ErbB4 is expressed specifically in interneurons and both in vitro and in vivo studies indicate that ErbB4 plays a critical role in the assembly of the GABAergic circuitry. On the other hand, NRG1 and ErbB4 are expressed in the adult brain; acute treatment with NRG1 increases GABA release in the cortex and hippocampus. Blocking NRG1/ErbB4 signaling reduces GABA release, increases the firing of pyramidal neurons, and enhances long term potentiation (LTP). ErbB4 mutant mice exhibit SZ-relevant behavioral deficits including impaired PPI and working memory. While these observations are exciting, several critical questions are raised. Despite NRG1 and ErbB4 are known to promote GABAergic transmission, a glaring gap in our understanding of their function in the brain is that little is known about exactly how NRG1 stimulates GABA release from interneurons. Are behavioral deficits observed in adult ErbB4 mutant mice due to abnormal neural development, or synaptic dysfunction in adulthood, or both? Can adult ErbB4 expression mitigate behavioral deficits and synaptic dysfunction? To address these questions, we 1) investigate mechanisms by which NRG1 promotes GABA release; 2) identify the critical time window for ErbB4 mutation to cause synaptic dysfunction and behavioral deficits; and 3) investigate the role of ErbB4 kinase activity in synaptic function and behavior by acute inhibition Results will provide proof-of-principle evidence that relevant SZ may be treatable by recovering or restoring ErbB4 expression or activity. Such information could be useful to studies of other SZ susceptibility genes and to development of novel therapeutic strategies of the devastating disorder.