Regulation of presynaptic release by Cdk5 during homeostatic plasticity

描述（由申请人提供）：神经系统通过调节神经元之间的连接强度以将活性保持在窄范围内来实现稳定性。这种“突触稳态”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是癫痫和成瘾等神经系统疾病的基础。突触内稳态是一个强大的现象，从无脊椎动物到哺乳动物都有，但所涉及的分子机制还没有很好的理解。为了研究参与突触稳态的分子，我们建议使用果蝇幼虫的神经肌肉接头（NMJ）作为模型系统。当受到改变肌肉兴奋性的遗传或药理学操作的挑战时，NMJ表现出强大的突触稳态。果蝇强大的遗传学允许快速和廉价的筛选候选分子途径。此外，神经和肌肉之间的高度定型的连接允许高度可重复的电生理和成像实验，测定突触功能。本研究的目的是调查的候选分子途径，是高度保守的从苍蝇到哺乳动物的作用。 初步研究表明细胞周期蛋白依赖性激酶5（Cdk 5）参与突触强度的稳态调节。有趣的是，最近几项来自哺乳动物系统的研究指出Cdk 5在调节突触释放中的作用，然而，所涉及的分子途径和机制尚不清楚。以下实验旨在解决Cdk5如何与突触处的分子相互作用以调节突触强度。

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.