NRG1-ErbB4 regulation of synaptic plasticity and behavior

NRG1-ErbB4 对突触可塑性和行为的调节

• 批准号: 9452123
• 负责人: Lin Mei
• 金额: $ 49.1万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9452123
• 关键词: Acute; Address; Adolescent; Adult; Affect; Alzheimer' s Disease; Anhedonia; Behavior; Behavioral; Brain; Brain Diseases; Cognitive deficits; Cost of Illness; Cyclic GMP; Delusions; Development; Disease; Emotions; ErbB4 gene; Exhibits; Functional disorder; Glare; Glutamates; Growth Factor; Hallucinations; Hippocampus (Brain); Impairment; In Vitro; Interneurons; Judgment; Lead; Light; Long-Term Potentiation; Mental disorders; Meta-Analysis; Molecular; Morphology; Mus; Mutant Strains Mice; Mutation; Neuregulin 1; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Nitric Oxide; Nitric Oxide Synthase Type I; Parkinson Disease; Pathologic; Pathway interactions; Perception; Phosphotransferases; Physiological; Play; Population; Population Heterogeneity; Process; Regulation; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Susceptibility Gene; Synapses; Synaptic Transmission; Synaptic plasticity; Time; behavioral impairment; critical period; experimental study; gamma-Aminobutyric Acid; genome wide association study; genome-wide; hippocampal pyramidal neuron; in vivo; neural circuit; neurodevelopment; neurotransmission; novel therapeutics; population based; public health relevance; receptor; risk variant; synaptic function; transmission process

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.

描述（由申请人提供）：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。它会改变大脑的感知、情感和判断的基本过程，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，因此仍然是最不了解的脑部疾病之一。SZ被认为是一种神经发育障碍，由神经发育过程中的问题引起，导致青少年和成人的神经传递和可塑性受损。虽然已经涉及到谷氨酸能和GABA能途径的功能减退，但对潜在的分子机制知之甚少。近年来，SZ易感基因的鉴定及其功能的研究已开始揭示其病理生理学。基于关联研究，神经调节蛋白1（NRG 1）（一种生长因子）及其受体ErbB 4都是不同人群中的SZ风险基因。这一观点得到了最近的荟萃分析、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，NRG 1和ErbB 4参与了神经发育的各个步骤。特别是，ErbB 4在中间神经元中特异性表达，体外和体内研究均表明ErbB 4在GABA能回路的组装中起关键作用。另一方面，NRG 1和ErbB 4在成年大脑中表达;用NRG 1急性治疗增加了皮质和海马中的GABA释放。阻断NRG 1/ErbB 4信号传导减少GABA释放，增加锥体神经元的放电，并增强长时程增强（LTP）。ErbB 4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NRG 1和ErbB 4促进GABA能传递，但我们对其在大脑中功能的理解存在明显差距，即对NRG 1如何刺激GABA从中间神经元释放知之甚少。在成年ErbB 4突变小鼠中观察到的行为缺陷是由于异常的神经发育，还是成年期的突触功能障碍，还是两者兼而有之？成人ErbB 4表达能否减轻行为缺陷和突触功能障碍？为了解决这些问题，我们1）研究NRG 1促进GABA释放的机制; 2）确定ErbB 4突变导致突触功能障碍和行为缺陷的关键时间窗;通过急性抑制研究ErbB 4激酶活性在突触功能和行为中的作用。主要证据表明，相关SZ可以通过恢复或恢复ErbB 4表达或活性来治疗。这些信息可能是有用的其他SZ易感基因的研究和发展的毁灭性疾病的新的治疗策略。

项目成果

An ErbB4-Positive Neuronal Network in the Olfactory Bulb for Olfaction.

嗅球中用于嗅觉的 ErbB4 阳性神经元网络。

• DOI: 10.1523/jneurosci.0131-22.2022
• 发表时间: 2022
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Tan,Zhibing;Liu,Zhipeng;Liu,Yu;Liu,Fang;Robinson,Heath;Lin,ThiriW;Xiong,Wen-Cheng;Mei,Lin
• 通讯作者: Mei,Lin

Caspase-3, shears for synapse pruning.

Caspase-3，用于突触修剪的剪刀。

• DOI: 10.1016/j.devcel.2014.03.010
• 发表时间: 2014
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Shen,Chengyong;Xiong,WenC;Mei,Lin
• 通讯作者: Mei,Lin

Neuregulin 1 and ErbB4 Kinase Actively Regulate Sharp Wave Ripples in the Hippocampus.

Neuregulin 1 和 ErbB4 激酶主动调节海马体中的尖锐波波纹。

• DOI: 10.1523/jneurosci.1022-21.2021
• 发表时间: 2022
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Robinson,HeathL;Tan,Zhibing;Santiago-Marrero,Ivan;Arzola,EmilyP;Dong,TimothyVladimir;Xiong,Wen-Cheng;Mei,Lin
• 通讯作者: Mei,Lin

α7 nicotinic acetylcholine receptors as therapeutic targets in schizophrenia: Update on animal and clinical studies and strategies for the future.

• DOI: 10.1016/j.neuropharm.2020.108053
• 发表时间: 2020-06-15
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Terry AV Jr;Callahan PM
• 通讯作者: Callahan PM

The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons.

• DOI: 10.1038/s41380-021-01137-7
• 发表时间: 2023-03
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Wang H;Cui W;Chen W;Liu F;Dong Z;Xing G;Luo B;Gao N;Zou WJ;Zhao K;Zhang H;Ren X;Yu Z;Robinson HL;Liu Z;Xiong WC;Mei L
• 通讯作者: Mei L