Neuregulin-1 regulation of neurotransmission

Neuregulin-1 神经传递调节

• 批准号: 8045504
• 负责人: Lin Mei
• 金额: $ 36.86万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-06 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045504
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Address; Affect; Aminobutyric Acids; Area; Attenuated; Biological; Brain; Cells; Cerebrospinal Fluid; EGF gene; Epidermal Growth Factor; ErbB4 gene; Functional disorder; General Population; Glutamate Decarboxylase; Goals; Health; Interneurons; Knowledge; Long-Term Potentiation; Mental disorders; Molecular Genetics; Mutant Strains Mice; NRG1 gene; Neuraxis; Neuregulin 1; Neuropil; Parvalbumins; Pathogenesis; Pathway interactions; Phenotype; Phosphatidylinositide 3-Kinase Inhibitor; Phosphatidylinositols; Phosphotransferases; Physiologic pulse; Physiological; Prefrontal Cortex; Protein Isoforms; Regulation; Risk; Role; Sampling; Schizophrenia; Short-Term Memory; Signal Transduction; Site; Slice; Structure; Susceptibility Gene; Synapsins; Synaptic plasticity; TNF-alpha converting enzyme; Transmembrane Domain; Tyrosine Kinase Domain; base; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; improved; insight; interest; mutant; neurotransmission; novel; overexpression; postsynaptic; receptor; research study; transmission process; vesicular GABA transporter

DESCRIPTION (provided by applicant): Our long-term goal is to understand the role of neuregulin1 (NRG1) and its receptor ErbB4 in neurotransmission, allowing for an improved understanding of their contribution to pathophysiology of schizophrenia. Both NRG1 and ErbB4 are susceptibility genes of this heritable and highly debilitating mental disorder that affects 1% of the general population. However, the biological basis of the increased risk with NRG1 and ErbB4 genes remains unclear. Recently, we demonstrated that NRG1 facilitates depolarization-induced GABA release in the prefrontal cortex (PFC) in a manner dependent on ErbB4, identifying a novel function of NRG1 } regulation of GABAergic transmission. While these preliminary observations are interesting and may provide insight into potential mechanisms by which the NRG1/ErbB4 signaling regulates pathogenesis of schizophrenia, more experiments are necessary to understand the role of NRG1 in the PFC. To this end, we proposed the following experiments. First, we will determine whether NRG1/ErbB4 regulates parvalbumin (PV)-positive GABAergic interneurons in the PFC. We will determine whether ErbB4 is expressed at terminals of PV-positive interneurons in the PFC and investigate whether NRG1 regulation of GABA release requires ErbB4 in PV-positive cells. Second, we will investigate mechanisms of NRG1/ErbB4 regulation of evoked GABA release. We will determine whether NRG1 regulation of evoked GABA release requires PI3 kinase, study if CYT-1 is able to rescue the phenotype in ErbB4 mutant slices, and investigate whether synapsin is a PI3 kinase- downstream target. Third, we will explore functions and underlying mechanisms of NRG1 regulation of evoked GABA release. We will determine whether the effect of NRG1 on pyramidal neuron activity require ErbB4 and PI3 kinase, characterize the effect of NRG1 on pyramidal neuron excitability, and investigate whether working memory are deficient in ErbB4 mutant mice. It is our hope that the proposed experiments will provide new insights into functions and underlying mechanisms of NRG1 in regulating activity- dependent GABA release. The results will likely to contribute to a better understanding of how this trophic factor and its receptor ErbB4 regulate pathogenesis of schizophrenia. PUBLIC HEALTH RELEVANCE: Our long-term goal is to understand the role of neuregulin1 (NRG1) and its receptor ErbB4 in pathophysiology of schizophrenia. This project is to investigate the novel functions of NRG1 and their underlying mechanisms. These studies will insight into potential mechanisms by which this trophic factor regulates synaptic plasticity. Such knowledge will contribute to a better understanding of pathogenesis of schizophrenia.

描述（由申请人提供）：我们的长期目标是了解Neuregulin1（NRG1）及其受体ERBB4在神经传递中的作用，从而提高了对它们对精神分裂症病理生理学的贡献的了解。 NRG1和ERBB4都是这种可遗传和高度衰弱的精神障碍的敏感性基因，影响了总人群的1％。但是，NRG1和ERBB4基因风险增加的生物学基础尚不清楚。最近，我们证明了NRG1以依赖ERBB4的方式促进去极化诱导的GABA释放（PFC），从而确定了NRG1}的新功能的GABA能传播的新功能。尽管这些初步观察很有趣，并且可能提供了对NRG1/ERBB4信号传导调节精神分裂症发病机理的潜在机制的见解，但需要更多的实验来了解NRG1在PFC中的作用。为此，我们提出了以下实验。首先，我们将确定NRG1/ERBB4是否调节PFC中的白细胞蛋白（PV）阳性GABA能中间神经元。我们将确定在PFC中PV阳性中间神经元的末端表达ERBB4，并研究GABA释放的NRG1调控是否需要PV阳性细胞中的ERBB4。其次，我们将研究诱发GABA释放的NRG1/ERBB4调节机制。我们将确定诱发GABA释放的NRG1调节是否需要PI3激酶，研究CYT-1是否能够营救ERBB4突变体切片中的表型，并研究突触素是否是PI3激酶 - 下游靶标。第三，我们将探索诱发GABA释放的NRG1调控的功能和基本机制。我们将确定NRG1对锥体神经元活性的影响是否需要ERBB4和PI3激酶，表征了NRG1对锥体神经元兴奋性的影响，并研究工作记忆是否缺乏ERBB4突变小鼠。我们希望所提出的实验将为NRG1的功能和基本机制提供新的见解，以调节依赖性的GABA释放。结果可能有助于更好地理解这种营养因子及其受体ERBB4如何调节精神分裂症的发病机理。公共卫生相关性：我们的长期目标是了解Neuregulin1（NRG1）及其受体ERBB4在精神分裂症的病理生理学中的作用。该项目是为了研究NRG1及其潜在机制的新功能。这些研究将深入了解这种营养因子调节突触可塑性的潜在机制。这种知识将有助于更好地理解精神分裂症的发病机理。