NRG1-ErbB4 regulation of synaptic plasticity and behavior

NRG1-ErbB4 对突触可塑性和行为的调节

基本信息

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
项目类别：
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&apos 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

项目摘要

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）是一种致命的精神疾病，影响了全球范围内约1％的人口，也是美国第七昂贵的疾病。它改变了引起幻觉，妄想，思想障碍，狂热和认知缺陷的基本大脑过程。与神经退行性疾病（如阿尔茨海默氏病和帕金森氏病）不同，SZ缺乏病理标志，因此仍然是最知名的脑部疾病之一。 SZ被认为是一种神经发育障碍，这是由于神经发育过程中的问题引起的，导致青少年和成人的神经传递和可塑性受损。尽管已经涉及谷氨酸能和GABA能途径的功能障碍，但基本的分子机制知之甚少。最近鉴定出SZ敏感性基因及其功能的研究已开始阐明其病理生理学。基于关联研究，Neuregulin 1（NRG1），一个生长因子及其受体ERBB4都是不同种群中的SZ风险基因。该概念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，NRG1和ERBB4的神经发育假设一致，与神经发育的各个步骤有关。特别是，ERBB4在中间神经元中特别表达，体外和体内研究表明ERBB4在GABA能回路的组装中起着至关重要的作用。另一方面，NRG1和ERBB4在成年大脑中表达。 NRG1急性治疗会增加皮质和海马中的GABA释放。阻断NRG1/ERBB4信号传导可减少GABA的释放，增加锥体神经元的发射，并增强长期增强（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。尽管这些观察结果令人兴奋，但提出了一些关键问题。尽管已知NRG1和ERBB4可以促进GABA能传播，但我们对它们在大脑中功能的理解的明显差距是，对于NRG1如何刺激中间神经元的GABA释放，知之甚少。由于神经发育异常或成年后的突触功能障碍而导致的成年ERBB4突变小鼠中的行为缺陷是吗？成年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突变引起突触功能障碍和行为缺陷的关键时间窗口； 3）研究ERBB4激酶活性在突触功能和通过急性抑制作用结果中的作用将提供原理证明证据，表明可以通过恢复或恢复ERBB4表达或活性来治疗相关的SZ。此类信息可能对其他SZ易感基因的研究以及毁灭性疾病的新型治疗策略的发展有用。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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

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

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
影响因子：
0
作者：
Robinson,HeathL;Tan,Zhibing;Santiago-Marrero,Ivan;Arzola,EmilyP;Dong,TimothyVladimir;Xiong,Wen-Cheng;Mei,Lin
通讯作者：
Mei,Lin

Tropisetron enhances recognition memory in rats chronically treated with risperidone or quetiapine.