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: 10517897
• 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/10517897
• 关键词: Brain; Brain Diseases; Chemosensitization; Cognition; Data; Dendrites; Disease; Electrophysiology (science); Equilibrium; Genetic Transcription; Glutamates; Health; Hippocampus (Brain); 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 Transduction; Slice; Structure; Synapses; Synaptic plasticity; Testing; Translating; Translational Regulation; Translations; Up-Regulation; Work; experience; experimental study; gene repression; gephyrin; in vivo; insight; neuronal circuitry; neuropsychiatry; neurotransmission; novel; novel therapeutic intervention; protein expression; receptor; relating to nervous system; synaptic function; synaptic inhibition; trafficking; transcription factor

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.

项目总结