Altered glutamate signaling in mouse model of familial hemiplegic migraine

家族性偏瘫性偏头痛小鼠模型中谷氨酸信号的改变

• 批准号: 9470790
• 负责人: Patrick Parker
• 金额: $ 2.95万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-01 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9470790
• 关键词: Action Potentials; Adult; Affect; Animals; Astrocytes; Auras; Behavioral; Brain; Cessation of life; Characteristics; Classic Migraine; Communication; Data; Diffuse; Disease; Electrodes; Event; Evoked Potentials; Excision; Extracellular Space; Familial Hemiplegic Migraine; Functional disorder; Genetic; Genetic Models; Glutamate Transporter; Glutamates; Image; Light; Maps; Migraine; Mus; Mutation; Na(+)-K(+)-Exchanging ATPase; Nature; Neurons; Neurotransmitters; Optics; Pharmacology; Phenotype; Preventive treatment; Probability; Process; Regulation; Reporting; Rest; Role; Sensory; Signal Transduction; Spreading Cortical Depression; Surface; Symptoms; Synapses; Synaptic Receptors; TAC1 gene; Techniques; Time; Training; Vibrissae; awake; base; career; extracellular; glutamatergic signaling; habituation; in vitro activity; in vivo; in vivo imaging; insight; mouse model; nervous system disorder; neural recruitment; neuromechanism; neuronal cell body; neurophysiology; neurotoxicity; neurotransmission; presynaptic; relating to nervous system; response; sensory cortex; sensory input; sensory stimulus; synaptic function; two-photon; uptake

Project Summary/Abstract Migraine is a pervasive neurological disorder affecting 12-15% of the general populace in the U.S. and is highly invasive, if not debilitating, to sufferers of attacks. The neurophysiology that underlies migraine, though, is poorly understood. Premonitory symptoms and altered cortical evoked responses in migraineurs between attacks suggests persistent changes in brain network function that somehow give rise to migraine. The precedent aura that heralds the attack in up to one-third of migraineurs corresponds with cortical spreading depression (CSD), a wave of neural and glial depolarization within the cortex. Our understanding of CSD initiation rests on dysfunctional regulation of extracellular K+ and the excitatory neurotransmitter, glutamate. The purpose of this proposal is to elucidate mechanism of altered brain network function in migraine by studying a genetic form of the disorder, Familial Hemiplegic Migraine, type 2 (FHM2). FHM2 is a mutation of a sodium-potassium ATPase found in astrocytes in adults that drives clearance of glutamate following neural release. This clearance of glutamate is required to maintain the fidelity and staccato nature of neuron-to-neuron communication. The first aim of this proposal is to determine whether this decrease in glutamate clearance significantly alters the time course of neural glutamate signaling. The approach uses state of the art in vivo imaging of glutamate in real time as a living mouse carrying the FHM2 mutation is given a sensory stimulus. Results from this aim will show whether basic neural signaling is altered in the genetic form of migraine. The second aim of this proposal is to determine the effects of slowed glutamate clearance on synaptic activity and neural processing. Increasing the duration of glutamate in the extracellular space following neural release increases the ability of glutamate to act on post-synaptic receptors and the probability of recruiting neural responses. Simultaneous optical and electrical recordings of glutamate and neural activity will determine the effect of slowed glutamate clearance on neural processing. The results of this study will provide mechanistic evidence of persistent changes in brain network processing in migraine, shedding light on the pathophysiology that gives rise to migraine events.

项目摘要/摘要 偏头痛是一种普遍存在的神经系统疾病，影响美国12%-15%的普通人群，其发病率很高 侵袭性的，如果不是使人虚弱的，对遭受攻击的人来说。然而，偏头痛背后的神经生理学并不理想。 明白了。偏头痛发作间期的先兆症状和皮质诱发反应改变 表明大脑网络功能的持续变化会以某种方式导致偏头痛。先例气场 这预示着多达三分之一的偏头痛患者的发作与皮质扩散性抑制(CSD)相对应， 大脑皮层内神经和神经胶质细胞的去极化波。我们对CSD印心的理解建立在 细胞外K+和兴奋性神经递质谷氨酸的调节失调。这样做的目的是 建议通过研究偏头痛的一种遗传形式来阐明偏头痛脑网络功能改变的机制 这种疾病是家族性偏瘫偏头痛，2型(FHM2)。FHM2是钠-钾ATPase的突变 在成人的星形胶质细胞中发现，在神经释放后驱动谷氨酸的清除。本通行证 谷氨酸是维持神经元间通讯的保真度和断断续续的本质所必需的。第一 这项建议的目的是确定谷氨酸清除量的减少是否显著改变了时间 神经谷氨酸信号的过程。该方法使用最先进的谷氨酸实时活体成像 作为一只携带FHM2突变的活小鼠，会受到感官刺激。这一目标的结果将显示 偏头痛的遗传形式是否改变了基本神经信号。这项建议的第二个目的是 确定谷氨酸清除减慢对突触活动和神经加工的影响。增加了 神经释放后谷氨酸在细胞外间隙的持续时间增加了谷氨酸的作用能力 关于突触后受体和招募神经反应的可能性。光电同时进行 谷氨酸和神经活动的记录将确定谷氨酸清除减慢对神经的影响 正在处理。这项研究的结果将为大脑网络的持续变化提供机制证据 偏头痛的处理，揭示了引起偏头痛事件的病理生理学。