Regulation of presynaptic release by Cdk5 during homeostatic plasticity

描述(申请人提供)：神经系统通过调节神经元之间连接的强度来实现稳定，以保持活动在一个狭窄的范围内。这种突触动态平衡被认为对神经系统的正常功能至关重要，而这一过程的破坏可能会导致癫痫和成瘾等神经疾病。突触动态平衡是一种从无脊椎动物到哺乳动物都被保存下来的强健现象，但其中涉及的分子机制还不是很清楚。为了研究参与突触动态平衡的分子，我们建议使用果蝇幼虫神经肌肉接头(NMJ)作为一个模型系统。当受到改变肌肉兴奋性的遗传或药物操作的挑战时，NMJ表现出强大的突触动态平衡。果蝇强大的遗传学使得快速、廉价地筛选候选分子途径成为可能。此外，神经和肌肉之间的高度刻板印象的连接允许高度重复性的电生理和成像实验，以分析突触功能。这项研究旨在研究从苍蝇到哺乳动物的一条高度保守的候选分子途径的作用。初步研究表明，细胞周期蛋白依赖性激酶5(CDK5)参与了突触强度的动态平衡调节。有趣的是，最近几项来自哺乳动物系统的研究表明，CDK5在调节突触释放中发挥了作用，然而，涉及的分子途径和机制尚不清楚。以下实验旨在研究CDK5如何与突触上的分子相互作用来调节突触强度。

DESCRIPTION (provided by applicant): The nervous system achieves stability by regulating the strength of connections between neurons to preserve activity within a narrow range. This 'synaptic homeostasis' is thought to be critical for the normal function of the nervous system, and disruption of this process may underlie neurological disorders such as epilepsy and addiction. Synaptic homeostasis is a robust phenomenon that is preserved from invertebrates to mammals, yet the molecular mechanisms involved are not well understood. To investigate the molecules involved in synaptic homeostasis, we propose to use the larval neuromuscular junction (NMJ) of Drosophila melanogaster as a model system. The NMJ exhibits robust synaptic homeostasis when challenged with genetic or pharmacological manipulations that alter excitability of the muscle. The formidable genetics of Drosophila allows for rapid and inexpensive screening of candidate molecular pathways. Furthermore, the highly stereotyped connectivity between nerve and muscle allows for highly reproducible electrophysiological and imaging experiments that assay synaptic function. This research aims to investigate the role of a candidate molecular pathway that is highly conserved from fly to mammal. Preliminary studies have implicated the cyclin dependent kinase 5 (Cdk5) in the homeostatic regulation of synaptic strength. Interestingly, several recent studies from mammalian systems point to a role for Cdk5 in regulating synaptic release, however, the molecular pathways and mechanisms involved are unknown. The following experiments are designed to address the how Cdk5 interacts with molecules at the synapse to regulate synaptic strength.