Neurotrophin-dependent regulation of voltage-gated sodium channels

电压门控钠通道的神经营养蛋白依赖性调节

• 批准号: 10443551
• 负责人: Fernanda Laezza
• 金额: $ 59.18万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443551
• 关键词: Area; Axon; Behavioral Paradigm; Biochemical; Biochemistry; Biological Assay; Biological Markers; Biological Psychiatry; Biophysics; Brain; Brain-Derived Neurotrophic Factor; Cell physiology; Cells; Cellular Assay; Co-Immunoprecipitations; Complement; Complex; Development; Disease; Electrophysiology (science); Ensure; Experimental Models; Fibroblast Growth Factor; Functional disorder; Future; Gene Transfer; Genetic; Glycogen Synthase Kinase 3; Grant; Image; In Vitro; Ion Channel; Knowledge; Lasers; Lead; Light; Link; Long-Term Potentiation; Luciferases; Macromolecular Complexes; Maps; Mediating; Methods; Microscopy; Molecular; Molecular Biology; National Institute of Mental Health; Neuronal Plasticity; Neurons; Nucleus Accumbens; Outcome Study; Pathway interactions; Pharmacology; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Plant Roots; Predictive Factor; Predisposition; Property; Proteins; Rattus; Regulation; Resolution; Rewards; Rodent; Role; Scanning; Signal Transduction; Site; Slice; Sodium Channel; Stimulus; Synapses; Therapeutic Intervention; Tropomyosin; Variant; Viral Vector; base; biomarker development; cellular imaging; cellular targeting; environmental enrichment for laboratory animals; fibroblast growth factor 6; fibroblast growth factor-14; in vivo; innovation; interest; multidisciplinary; neuropsychiatric disorder; neurotrophic factor; novel; patch clamp; prevent; protein protein interaction; public health relevance; receptor; reconstitution; resilience; response; social; subcellular targeting; therapeutically effective; voltage

ABSTRACT Neuropsychiatric disorders are thought to arise from complex changes of brain plasticity. Recent evidence points toward ion channel complexes as cellular hubs of plasticity that confer disease vulnerability or protection depending on the channel regulatory state. In medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a subtype of highly vulnerable cells, neuroadaptive changes in intrinsic firing are mediated by neurotrophin brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling. Yet, the molecular mechanisms by which these changes occur are still poorly understood. Intrinsic firing in MSN relies on the integrity of the macromolecular complex of the voltage-gated Na+ (Nav) channel Nav1.6 and its accessory regulatory fibroblast growth factor 14 (FGF14) and is subject to regulation by glycogen synthase kinase 3 (GSK3) β, a downstream effector of BDNF/TrkB signaling. Here, we provide exciting new evidence for the Nav1.6, FGF14 and GSK3β as a macromolecular signaling complex downstream of BDNF/TrkB critical for MSNs neuronal plasticity. Using an array of in vitro and in cell assays, cell imaging, and electrophysiology, we show that stability, phosphorylation and functional activity of the Nav1.6 channel are proportional to the level of BDNF and the kinase activity, whereby low level of BDNF predicts resilience and high level mediates a susceptible phenotype conferred by changes in neuron firing. We will conduct a full range of biophysical, biochemical and electrophysiological studies combined with pharmacological and viral vector-based in vivo gene transfer methods to evaluate the impact of BDNF/TrkB signaling on macromolecular composition (Aim 1), subcellular targeting (Aim 2) and functional properties (Aim 3) of the Nav1.6 channel in the context of neuroadaptive plasticity of MSNs. Outcomes of these studies could potentially lead to the development of biomarkers of susceptibility to neuropsychiatric disorders by investigating molecular pathways in relevant experimental models, an area of great interest for biological psychiatry.

抽象的 神经精神疾病被认为是由脑可塑性的复杂变化引起的。最近的证据 将离子通道复合物指向可塑性的细胞枢纽，即会议疾病脆弱性或保护 取决于渠道调节状态。在伏隔核（NAC）中的中刺神经元（MSN）中， 高度脆弱的细胞的亚型，内在触发的神经适应性变化是由神经营养素介导的 脑衍生的神经营养因子（BDNF）/tropomyosin受体激酶B（TRKB）信号传导。 但是，分子 这些变化发生的机制仍然很少了解。 MSN中的固有发射取决于电压门控na+（NAV）的大分子复合物的完整性 通道NAV1.6及其附属调节成纤维细胞生长因子14（FGF14），并受到调节 糖原合酶激酶3（GSK3）β，BDNF/TRKB信号的下游效应子。在这里，我们提供 令人兴奋的NAV1.6，FGF14和GSK3β作为下游大分子信号复合物的新证据 BDNF/TRKB的MSN神经元可塑性至关重要。使用一系列体外和细胞分析，细胞成像， 和电生理学，我们表明NAV1.6通道的稳定性，磷酸化和功能活性为 与BDNF和激酶活性的水平成正比，从而低水平 BDNF预测弹性和 高水平介导神经输血变化所赋予的易感表型。我们将进行全面 生物物理，生化和电生理研究范围与药物和病毒结合 基于矢量的体内基因转移方法评估BDNF/TRKB信号对大分子的影响 组成（AIM 1），亚细胞靶向（AIM 2）和功能特性（AIM 3） MSN的神经适应性可塑性的背景。这些研究的结果可能会导致 通过研究分子途径来发展具有神经精神疾病的易感性的生物标志物 在相关的实验模型中，这是生物精神病学的极大兴趣领域。