Local translation mechanisms to control inhibitory synaptic plasticity

项目摘要 大脑中的突触抑制主要是由GABA能抑制性突触介导的，而GABA能抑制性突触在 控制神经元放电，神经元和回路的兴奋性，以及突触的可塑性。抑制性突触经历 多种可塑性模式，但驱动持续性抑制性突触后可塑性的分子机制 仍然没有明确的定义。由于突触蛋白的翻译对许多形式的可塑性是必不可少的，因此合成 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发挥关键作用。 然而，关于哪些抑制性突触蛋白被翻译，它们在哪里产生，以及 这一过程是如何在活动中被调节的。我们的初步工作表明，多重抑制性突触 在抑制性长时程增强过程中，蛋白质在神经元树突中被局部翻译。这一过程是紧密的 受miRNAs调控，翻译的强大负调节因子。这项提案将审查对 在体内和体外通过局部miRNA依赖的翻译调节抑制突触可塑性 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的持久和持久变化的关键机制。vt.给出 抑制性突触在大脑中的重要作用，这个项目将提供对潜在的 学习、记忆和认知的机制。

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.