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，也是美国第七大最昂贵的疾病。它改变大脑的感知、情感和判断的基本过程，导致幻觉、妄想、思维障碍、快感缺失和认知缺陷。与阿尔茨海默病和帕金森病等神经退行性疾病不同，精神分裂症缺乏病理特征，因此仍然是人们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导致青少年和成人的神经传递和可塑性受损。尽管谷氨酸能和 GABA 能途径的功能减退已被证实，但其潜在的分子机制仍知之甚少。最近对 SZ 易感基因的鉴定及其功能研究已开始揭示其病理生理学。根据关联研究，生长因子神经调节蛋白 1 (NRG1) 及其受体 ErbB4 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，NRG1 和 ErbB4 与神经发育的各个步骤有关。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 能电路的组装中发挥着关键作用。另一方面，NRG1和ErbB4在成人大脑中表达； NRG1 的急性治疗会增加皮质和海马体中 GABA 的释放。阻断 NRG1/ErbB4 信号传导可减少 GABA 释放，增加锥体神经元的放电，并增强长时程增强 (LTP)。 ErbB4 突变小鼠表现出与 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，但也提出了一些关键问题。尽管 NRG1 和 ErbB4 已知可促进 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，即我们对 NRG1 究竟如何刺激中间神经元释放 GABA 知之甚少。成年 ErbB4 突变小鼠中观察到的行为缺陷是否是由于神经发育异常或成年期突触功能障碍或两者兼而有之？成人 ErbB4 表达可以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口； 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。结果将提供原理验证证据，表明相关的 SZ 可以通过恢复或恢复 ErbB4 表达或活性来治疗。这些信息可能有助于研究其他 SZ 易感基因，并有助于开发这种破坏性疾病的新治疗策略。

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