Neuregulin-1 regulation of neurotransmission

描述(申请人提供)：我们的长期目标是了解神经调节蛋白1(NRG1)及其受体ErbB4在神经传递中的作用，从而更好地了解它们在精神分裂症病理生理学中的贡献。NRG1和ErbB4都是这种可遗传的高度衰弱的精神疾病的易感基因，影响1%的普通人口。然而，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以一种依赖于ErbB4的方式促进去极化诱导的前额叶皮质(PFC)中GABA的释放，确认了NRG1调节GABA能传递的新功能。虽然这些初步观察是有趣的，并可能为深入了解NRG1/ErbB4信号调节精神分裂症发病的潜在机制提供线索，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内小白蛋白(PV)阳性的GABA能中间神经元。我们将确定ErbB4是否在PFC中PV阳性中间神经元的终末表达，并研究NRG1对GABA释放的调节是否需要在PV阳性细胞中表达ErbB4。其次，我们将研究NRG1/ErbB4对GABA释放的调节机制。我们将确定NRG1对诱导的GABA释放的调节是否需要PI3激酶，研究CyT-1是否能够挽救ErbB4突变切片中的表型，并调查突触素是否是PI3激酶下游的靶点。第三，我们将探索NRG1调节诱发性GABA释放的功能和潜在机制。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NRG1对锥体神经元兴奋性的影响，并调查ErbB4突变小鼠是否存在工作记忆缺陷。我们希望拟议的实验将为NRG1调节活性依赖的GABA释放的功能和潜在机制提供新的见解。这一结果可能有助于更好地理解这种营养因子及其受体ErbB4如何调控精神分裂症的发病机制。公共卫生相关性：我们的长期目标是了解神经调节蛋白1(NRG1)及其受体ErbB4在精神分裂症病理生理学中的作用。本项目旨在研究NRG1的新功能及其潜在的机制。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。这些认识将有助于更好地理解精神分裂症的发病机制。

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.