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 作为细胞功能的必需元素，二价锌是许多酶和 调节蛋白。自从令人惊讶的发现锌集中在许多突触小泡中 大脑中的兴奋性突触，包括超过50%的新皮质兴奋性突触前终末 在这些区域，许多研究人员研究了这种金属在神经传递过程中的可能作用。 尽管如此，由于用于神经生物学研究的锌选择工具的匮乏，生理学 直到最近，锌在突触传递中的作用仍然难以捉摸。我们最近的研究，是由这个资助的 Grant，使用了新的工具来螯合和跟踪中央突触中的锌，并确定锌是一种抑制作用 兴奋性突触中的神经调节剂。作为对单个突触前动作电位的反应，突触锌是 释放并抑制突触后谷氨酸AMPA受体(AMPAR)。此外，在重复突触过程中 刺激时，锌抑制突触外谷氨酸NMDA受体(NMDAR)，并与 GPR39，一个可能的代谢性锌敏感受体，激活内源性大麻素信号和 抑制谷氨酸释放。这些效果依赖于经验，因为响亮的声音会减少 突触前锌水平和取消锌对AMPAR的抑制，提示锌在经验依赖中的作用 安帕尔突触可塑性。一种新型内源性神经调节剂的建立，作用于许多 兴奋性突触遍布大脑，揭示了这项工作的意义，并提出了三个问题 兴奋性突触信号和听觉处理的基本重要性：a)什么是动力学 锌介导的抑制作用的不同形式及其相互作用和与谷氨酸的相互作用 神经传递形成兴奋性谷氨酸能信号，b)分子机制是什么 突触前锌水平潜在的长期、活动依赖性变化及其相互作用 其他已建立的可塑性机制，以及c)触发锌的听觉刺激的特征是什么 体内释放以及锌释放如何影响清醒动物的自发和声音诱发活动。 回答这些问题将不仅对锌生物学和听力领域做出重大贡献 研究，但也将揭示一般机制，这将是更广泛的神经科学的极大兴趣 社区。在目标1和目标2中，我们将使用体外脑片实验和听觉脑干 突触作为研究锌在神经传递和可塑性中作用的模型。在目标3中，我们将使用 在体显像研究这些机制在非麻醉大鼠听皮层加工中的作用 老鼠。