Neuregulin-1 regulation of neurotransmission

描述（由申请人提供）：我们的长期目标是了解神经调节蛋白1（NRG 1）及其受体ErbB 4在神经传递中的作用，从而更好地了解它们对精神分裂症病理生理学的贡献。NRG 1和ErbB 4都是这种可遗传且高度衰弱的精神障碍的易感基因，影响着1%的普通人群。然而，NRG 1和ErbB 4基因增加风险的生物学基础仍不清楚。最近，我们证明NRG 1以依赖于ErbB 4的方式促进前额叶皮层（PFC）中去极化诱导的GABA释放，从而鉴定了NRG 1调节GABA能传递的新功能。虽然这些初步的观察是有趣的，并可能提供洞察的潜在机制，NRG 1/ErbB 4信号调节精神分裂症的发病机制，更多的实验是必要的，以了解NRG 1在PFC的作用。为此，我们提出了以下实验。首先，我们将确定NRG 1/ErbB 4是否调节PFC中的小白蛋白（PV）阳性GABA能中间神经元。我们将确定ErbB 4是否在PFC中的PV阳性中间神经元的末端表达，并调查NRG 1对GABA释放的调节是否需要PV阳性细胞中的ErbB 4。其次，我们将研究NRG 1/ErbB 4调节诱发GABA释放的机制。我们将确定NRG 1对诱发GABA释放的调节是否需要PI 3激酶，研究CYT-1是否能够拯救ErbB 4突变切片中的表型，并研究突触蛋白是否是PI 3激酶下游靶点。第三，我们将探讨NRG 1的功能和潜在的机制，诱发GABA释放的调节。我们将确定NRG 1对锥体神经元活动的影响是否需要ErbB 4和PI 3激酶，表征NRG 1对锥体神经元兴奋性的影响，并调查ErbB 4突变小鼠的工作记忆是否存在缺陷。我们希望这些实验能为NRG 1调节活动依赖性GABA释放的功能和机制提供新的认识。这一结果将有助于更好地了解这种营养因子及其受体ErbB 4如何调节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素1（NRG 1）及其受体ErbB 4在精神分裂症病理生理中的作用。本项目旨在研究NRG 1的新功能及其作用机制。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。这些知识将有助于更好地了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.