Retrograde Regulation of Synaptic Strength by Translational Mechanisms

描述（由申请人提供）：突触强度的适当调节对于维持神经回路的稳定性至关重要。这一规定取决于以下方面的平衡： 促进突触功能响应细胞外和细胞内线索的变化的分子机制，以及寻求在正常范围内调节神经元功能的稳态机制，确保神经回路的稳定性1 -2。这个提议旨在解开有助于突触稳态机制的分子组成和机制。我的团队一直在利用果蝇幼虫神经肌肉接头（NMJ）作为突触模型。当突触后功能在该突触处降低时，在突触后肌肉中启动稳健的稳态逆行信号，其反馈到突触前运动神经元以引起突触前神经递质释放的补偿性增强1。NMJ是一个特别适合研究这种反馈或逆行信号传导机制的模型，因为果蝇的短生命周期以及果蝇中强大的遗传学允许有效地识别和表征参与这种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研究结果表明，控制从头蛋白质合成的翻译机制对于NMJ诱导神经递质释放中的这种逆行补偿的能力至关重要。此外，我们有强有力的初步数据表明，帕金森病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靶点，这可能进一步揭示了TIS信号转导的本质。我们的研究计划是基于丰富的初步数据和未发表的意见，并利用多学科的方法，结合果蝇遗传学与分子生物学，生物化学，成像和电生理学。我们有一个独特的机会来了解逆行信号如何在突触上运作，以诱导稳态效应。鉴于这些信号分子的高度保守性，我们的研究结果有望被转化为高等生物，并为未来旨在解决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 In particular, our recently published work3 as well a wealth of unpublished preliminary findings indicate that translational mechanism that control do novo protein synthesis are essential for the ability of the NMJ to induce this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.