Synaptic Function in the Nematode C. Elegans

 描述（由申请人提供）：神经细胞之间的通信通过在突触处释放神经递质来进行。信号传递可以非常迅速-每秒通过数百个动作电位传递信息。以这种速度合成新的突触囊泡是不可能的，因此快速循环是必不可少的。虽然突触的内吞作用是突触传递的核心，但关于其机制的争论已经持续了40多年而没有解决。我们最近发现，在线虫C. elegans和小鼠海马神经元发生的速度为50 ms，而不是先前确定的20秒。我们的初步结果表明，这一过程需要聚合肌动蛋白和肌球蛋白-II。我们的每一个目标都将包括海马神经元的药理学研究和C。elegans特定的分子靶点。目标1.肌动蛋白在膜内陷中的作用可能是通过活性聚合、稳定的肌动蛋白丝、分支的肌动蛋白或稳定的皮质肌动蛋白板。目标2.将在海马神经元和C.优雅目标3：形成/透明蛋白质包裹肌动蛋白丝并与肌球蛋白-II起作用。目标4。Rho直接激活形成蛋白，Rho通过激酶ROCK激活肌球蛋白-II。目标5。目前尚不清楚超快内吞作用是否仅回收膜或是否也从表面回收突触囊泡蛋白。我们将标记突触囊泡蛋白质的内腔侧，并确定它们是否被纳入内吞囊泡。越来越多的证据表明，了解内吞作用将对应用健康研究产生直接影响，因为内吞作用的缺陷可能在神经元疾病中起致病作用，包括亨廷顿病、共济失调、帕金森病、赫-普综合征和阿尔茨海默病。我们希望，了解内吞作用的过程可能会导致这些疾病的药物治疗在未来。最后，我们正在开发创新的新技术，通过为这些和其他问题带来新武器来帮助其他研究人员。

 DESCRIPTION (provided by applicant): Communication between nerve cells takes place by the release of neurotransmitters at synapses. Signaling can be extremely rapid - transmitting information via hundreds of action potentials per second. It is not possible to synthesize new synaptic vesicles at this pace, so rapid recycling is essential. Although endocytosis at the synapse is at the core of synaptic transmission, the debate about the mechanism has continued for over 40 years without resolution. We recently discovered that synaptic vesicle endocytosis at synapses in the nematode C. elegans and mouse hippocampal neurons occurs as rapidly as 50 ms rather than 20 seconds, as determined previously. Our preliminary results suggest that this process requires polymerized actin and myosin-II. Each one of our aims will incorporate pharmacological studies in hippocampal neurons and genetic studies in C. elegans on particular molecular targets. Aim 1. The role for actin in membrane invagination could be via active polymerization, stable actin filaments, branched actin, or stable cortical actin plates. Aim 2. Myosin-II function in ultrafast endocytosis will be tested in hippocampal neurons and in C. elegans. Aim 3. The forming / diaphanous proteins polymerize actin filaments and function with myosin-II. Aim 4. Rho activates Formin directly, and Rho activates Myosin-II via the kinase ROCK. Aim 5. It is not known whether ultrafast endocytosis only retrieves membrane or whether it also retrieves synaptic vesicle proteins from the surface. We will tag the lumenal side of synaptic vesicle proteins and determine whether they are incorporated into endocytic vesicles. There is growing evidence that understanding endocytosis will have direct impact on applied health research, since defects in endocytosis may play causative roles in neuronal diseases, including Huntington's Disease, the ataxias, Parkinson's Disease, Hermansky-Pudlack syndrome, and Alzheimer's Disease. It is our hope that understanding the process of endocytosis may lead to drug therapies for these diseases in the future. Finally, we are developing innovative new techniques that will aid other researchers by bringing new weapons to these and other problems.