Local translation mechanisms to control inhibitory synaptic plasticity

控制抑制性突触可塑性的局部翻译机制

• 批准号: 10670420
• 负责人: Katharine Rachel Smith
• 金额: $ 49.06万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670420
• 关键词: Behavior; Brain; Brain Diseases; Chemosensitization; Cognition; Data; Dendrites; Disease; Electrophysiology (science); Equilibrium; Genetic Transcription; Glutamates; Health; Hippocampus; Image; In Vitro; Inhibitory Synapse; Learning; Long-Term Potentiation; Mediating; Memory; Messenger RNA; Methods; MicroRNAs; Molecular; N-Methyl-D-Aspartate Receptors; Neurons; Pathology; Pathway interactions; Phase; Play; Process; Proteins; Regulation; Role; Scaffolding Protein; Sensory; Signal Repression; Signal Transduction; Site; Slice; Structure; Synapses; Synaptic plasticity; Testing; Translating; Translational Regulation; Translations; Up-Regulation; Work; experience; experimental study; gene repression; gephyrin; in vivo; insight; neural; neuronal circuitry; neuropsychiatry; neurotransmission; novel; novel therapeutic intervention; nuclear factors of activated T-cells; postsynaptic; protein expression; receptor; synaptic function; synaptic inhibition; trafficking

Project Summary Synaptic inhibition in the brain is mostly mediated by GABAergic inhibitory synapses, which are essential in controlling neuronal firing, neuron and circuit excitability, and synaptic plasticity. Inhibitory synapses undergo multiple modes of plasticity but the molecular mechanisms that drive persistent inhibitory post-synaptic plasticity remain poorly defined. As translation of synaptic proteins is essential for many forms of plasticity, synthesis of new inhibitory post-synaptic proteins likely plays a key role in sustaining changes in inhibitory synaptic strength. However, little is known about which inhibitory synaptic proteins are translated, where they are produced and how this process is regulated during activity. Our preliminary work suggests that multiple inhibitory synaptic proteins are locally translated in neuronal dendrites during inhibitory long-term potentiation. This process is tightly regulated by miRNAs, potent negative-regulators of translation. This proposal will examine the control of inhibitory synaptic plasticity by local miRNA-dependent translational regulation, using in vivo and in vitro advanced imaging and electrophysiological approaches. The proposed studies are significant as they have the potential to reveal key mechanisms that drive persistent and long-lasting changes in synaptic inhibition. Given the important roles of inhibitory synapses in the brain, this project will provide crucial insight into the underlying mechanisms of learning, memory and cognition.

项目摘要 脑中的突触抑制主要由GABA能抑制性突触介导，其在神经系统中是必需的。 控制神经元放电、神经元和回路兴奋性以及突触可塑性。抑制性突触经历 可塑性的多种模式，但驱动持续抑制性突触后可塑性的分子机制 定义不明确。由于突触蛋白的翻译对于许多形式的可塑性是必不可少的， 新的抑制性突触后蛋白可能在维持抑制性突触强度的变化中起关键作用。 然而，很少有人知道哪些抑制性突触蛋白被翻译，它们在哪里产生， 这个过程在活动中是如何调节的。我们的初步工作表明，多抑制性突触 蛋白质在抑制性长时程增强期间在神经元树突中局部翻译。这个过程是紧密的 由miRNAs调节，这是一种有效的翻译负调节因子。这项建议将研究管制 通过局部miRNA依赖性翻译调节抑制突触可塑性，在体内和体外使用 先进的成像和电生理方法。拟议的研究具有重要意义，因为它们具有 有可能揭示驱动突触抑制持续和持久变化的关键机制。给定 抑制性突触在大脑中的重要作用，这个项目将提供关键的洞察到潜在的 学习记忆和认知的机制