Retrograde Regulation of Synaptic Strength by Translational Mechanisms

描述(由申请人提供)：适当调节突触强度对于维持神经回路的稳定性至关重要。这项规定的关键在于平衡 促进突触功能改变以响应细胞外和细胞内信号的分子机制，以及寻求在正常范围内调整神经元功能的动态平衡机制，以确保神经回路1-2的稳定性。这一提议旨在解开有助于突触内稳机制的分子成分和机制。我的团队一直在利用果蝇幼虫神经肌肉接头(NMJ)作为突触的模型。当这个突触的突触后功能降低时，一个强大的稳态逆行信号在突触后肌肉中启动，反馈到突触前运动神经元，导致突触前神经递质释放的代偿性增强。NMJ是研究这种反馈或逆行信号机制的特别合适的模型，因为果蝇短的生命周期和强大的遗传学允许有效地识别和表征参与这一协调过程的基因和机制。特别是，我们最近发表的工作3以及大量未发表的初步发现表明，控制新蛋白质合成的翻译机制对于NMJ在神经递质释放中诱导这种逆行补偿的能力是必不可少的。此外，我们有强有力的初步数据表明，帕金森氏症相关基因与翻译机制相互作用，从而影响NMJ的突触传递。我们还确定了突触后翻译的潜在翻译目标，这可能进一步揭示TIS信号的性质。我们的研究计划基于丰富的初步数据和未发表的观察结果，并利用多学科方法，将果蝇遗传学与分子生物学、生物化学、成像和电生理学相结合。我们有一个独特的机会来理解逆行信号是如何在突触上运作的，以诱导内环境平衡效应。鉴于这些信号分子的高度保守性质，我们的发现有望被翻译成更高层次的生物体，并为未来旨在治疗神经系统疾病的治疗方法铺平道路。

DESCRIPTION (provided by applicant): Appropriate regulation of synaptic strength is essential for maintaining stability in neural circuits. This regulation hinges on a balance between molecular mechanisms that promote change in synaptic function in response to extracellular and intracellular cues, and homeostatic mechanisms that seek to adjust neuronal function within a normal range, ensuring stability in neural circuits circuits1-2. This proposal is designed to unravel molecular components and mechanisms that contribute to homeostatic mechanisms at the synapse. My group has been taking advantage of the Drosophila larval neuromuscular junction (NMJ) as a model synapse. When postsynaptic function is reduced at this synapse, a robust homeostatic retrograde signal is initiated in the postsynaptic muscles, which feeds back to the presynaptic motor neuron to cause a compensatory enhancement in presynaptic neurotransmitter release1. The NMJ is a particularly well-suited model for studying this feedback or retrograde signaling mechanism, since the short life cycle of flies together with the powerful genetics available in Drosophila allow for an efficient identification and characterizatio of genes and mechanisms that participate in this coordinated process. In particular, our recently published work3 as well a wealth of unpublished preliminary findings indicate that translational mechanism that control do novo protein synthesis are essential for the ability of the NMJ to induce this retrograde compensation in neurotransmitter release. In addition, we have strong preliminary data that a Parkinson's related genes interacts with translational mechanisms and thereby influences synaptic transmission at the NMJ. We have also identified potential translational targets for postsynaptic translation that may further shed light into the nature of tis signaling. Our research plan is based on a wealth of preliminary data and unpublished observations and utilizes a multidisciplinary approach that combines Drosophila genetics with molecular biology, biochemistry, imaging and electrophysiology. We have a unique opportunity for understanding how retrograde signaling operates at synapses to induce homeostatic effects. In light of the highly conserved nature of these signaling molecules, our findings hold the promise of being translated to higher organisms and pave the way for future therapeutic approaches aimed at tackling nervous system diseases.