Cell-specific Synaptic Plasticity in the Auditory Brainstem

听觉脑干中的细胞特异性突触可塑性

• 批准号: 9236791
• 负责人: Thanos Tzounopoulos
• 金额: $ 56.82万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-08 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236791
• 关键词: AMPA Receptors; Action Potentials; Affect; Alzheimer' s Disease; Anatomy; Animals; Area; Auditory; Auditory area; Biochemical; Biology; Brain; Brain Stem; Cell physiology; Cells; Characteristics; Chelating Agents; Communities; Disease; Electrophysiology (science); Elements; Enzymes; Epilepsy; Excitatory Synapse; Exposure to; Frequencies; Funding; GPR39 gene; Genetic; Glutamate Receptor; Glutamates; Grant; Health; Hearing; Image; Imaging Techniques; In Vitro; Individual; Knockout Mice; Label; Lead; Long-Term Depression; Loudness; Measures; Mediating; Metals; Mission; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neurobiology; Neuromodulator; Neurons; Neurosciences; Nitric Oxide; Pain; Pharmacology; Physiological; Presynaptic Terminals; Probability; Receptor Activation; Research; Research Personnel; Role; Schizophrenia; Shapes; Signal Transduction; Slice; Study models; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Techniques; Testing; Tinnitus; United States National Institutes of Health; Work; Zinc; auditory processing; auditory stimulus; awake; base; calcium indicator; cofactor; disability; endocannabinoid signaling; experience; experimental study; genetic regulatory protein; glutamatergic signaling; imaging approach; improved; in vivo; in vivo imaging; interest; neocortical; neurotransmission; novel; postsynaptic; presynaptic; relating to nervous system; response; restoration; signal processing; sound; tool; two-photon

Project Summary As an essential element for cellular function, divalent zinc is a cofactor in a large number enzymes and regulatory proteins. Since the surprising discovery that zinc is concentrated within synaptic vesicles in many excitatory synapses in the brain, including in more than 50% of excitatory presynaptic terminals in neocortical areas, numerous investigators have studied the possible roles of this metal during neurotransmission. Nonetheless, due to the paucity of zinc–selective tools optimized for neurobiological studies, the physiological roles of zinc during synaptic transmission remained elusive until recently. Our recent studies, funded by this grant, used novel tools for chelating and tracking zinc in central synapses and established zinc as an inhibitory neuromodulator in excitatory synapses. In response to a single presynaptic action potential, synaptic zinc is released and inhibits postsynaptic glutamate AMPA receptors (AMPARs). Moreover, during repetitive synaptic stimulation, zinc inhibits extrasynaptic glutamate NMDA receptors (NMDARs) and is necessary along with GPR39, a putative metabotropic zinc-sensing receptor, for activation of endocannabinoid signaling and glutamate release inhibition. These effects are experience-dependent because loud sound reduced presynaptic zinc levels and abolished zinc inhibition of AMPARs, implicating zinc in experience-dependent AMPAR synaptic plasticity. The establishment of a novel endogenous neuromodulator, acting in many excitatory synapses throughout the brain, reveals the significance of the work and poses three questions of fundamental importance to excitatory synaptic signaling and auditory processing: a) what are the dynamics of the different forms of zinc-mediated inhibition and how do they interact among themselves and with glutamate neurotransmission to shape excitatory glutamatergic signaling, b) what are the molecular mechanisms underlying long-lasting, activity-dependent changes in presynaptic zinc levels and how do they interact with other established plasticity mechanisms, and c) what are the characteristics of auditory stimuli that trigger zinc release in vivo and how does zinc release affect spontaneous and sound-evoked activity in awake animals. Answering these questions will contribute significantly not only to the fields of zinc biology and hearing research, but will also reveal general mechanisms that will be of great interest to the wider neuroscience community. In Aims 1 and 2, we will employ in vitro brain slice experiments and use auditory brainstem synapses as models for studying the role of zinc in neurotransmission and plasticity. In Aim 3, we will employ in vivo imaging to investigate the role of these mechanisms in auditory cortical processing in unanesthetized mice.

项目摘要 作为细胞功能的重要元素，二价锌是大数酶中的辅助因子，并且 调节蛋白。由于令人惊讶的发现锌集中在许多人中的突触蔬菜中 大脑中的兴奋性突触，包括在新皮层中超过50％的兴奋性突触前终端 许多研究人员研究了这种金属在神经传递中的可能作用。 尽管如此，由于对神经生物学研究优化的锌选择性工具的缺乏，生理 直到最近，锌在突触传播过程中的作用仍然难以捉摸。我们最近的研究，由此资助 格兰特（Grant 兴奋性突触中的神经调节剂。响应单个突触前动作电位，突触锌为 释放并抑制突触后谷氨酸AMPA受体（AMPARS）。而且，在重复的突触中 刺激，锌抑制外斜肌NMDA受体（NMDAR），并且是必要的 GPR39，一种推定的代谢锌感应受体，用于激活内源性大麻素信号传导和 谷氨酸释放抑制。这些效果依赖于经验，因为大声的声音降低了 突触前锌水平和废除对AMPAR的锌抑制，与经验有关的隐式锌 AMPAR突触可塑性。建立一种新型的内源性神经调节剂，作用于许多 整个大脑的兴奋性突触揭示了工作的重要性，并提出了三个问题 对兴奋性突触信号和听觉处理的基本重要性：a）什么是什么动态 锌介导的不同形式的抑制作用，以及它们如何相互作用以及与谷氨酸 神经传递以塑造兴奋性谷氨酸能信号传导，b）分子机制是什么 潜在的长期持久，活动依赖性的突触前锌水平的变化，以及它们如何与之相互作用 其他已建立的可塑性机制，c）触发锌的听觉刺激的特征是什么 在体内释放，锌释放如何影响清醒动物的赞助和声音诱发的活动。 回答这些问题不仅会对锌生物学领域和听力产生重大贡献 研究，但还将揭示一般机制，这将引起更广泛的神经科学的兴趣 社区。在目标1和2中，我们将采用体外脑切片实验并使用听觉脑干 突触是研究锌在神经传递和可塑性中的作用的模型。在AIM 3中，我们将雇用 体内成像，以研究这些机制在听觉皮质加工中的作用 老鼠。