Molecular mechanisms of presynaptic membrane recycling, turnover, and transport

大脑功能关键取决于化学突触的神经传递，而突触功能障碍导致癫痫、精神分裂症、自闭症和痴呆等疾病。神经递质的释放是由钙触发的突触囊泡（SV）在活动区的融合介导的，随后是内吞膜的回收和SV的重组。尽管几十年的研究基本问题，突触前内吞作用的机制，外吞平衡的维持，突触前膜成分的营业额，以及突触前功能的质量控制耦合的机制是没有答案的。在拟议的项目中，我们的目标是阐明耦合突触前的外吞作用，调节膜周转和运输通过自噬-溶酶体途径的分子机制。光遗传学、细胞生物学、生物化学和高分辨率成像方法将与遗传学、电生理学和行为学研究相结合，以揭示突触前功能如何在分子上与质量控制机制相联系，从而在大脑的一生中维持神经传递。我们的研究对于理解突触的功能和维护以及开发治疗方法以对抗神经系统和神经退行性疾病具有根本重要性。

Brain function crucially depends on neurotransmission at chemical synapses, while synaptic dysfunction leads to diseases ranging from epilepsy, schizophrenia and autism to dementia. Neurotransmitter release is mediated by calcium-triggered fusion of synaptic vesicles (SVs) at the active zone, followed by endocytic membrane retrieval and SV reformation. In spite of decades of research basic questions concerning the mechanisms of presynaptic endocytosis, the maintenance of exo-endocytic balance, the turnover of presynaptic membrane components, and the mechanisms that couple presynaptic function to quality control are unanswered. Within the proposed project we aim to elucidate the molecular mechanisms that couple presynaptic exo-endocytosis to regulated membrane turnover and transport via the autophagy-lysosomal pathway. Optogenetic, cell biological, biochemical, and high-resolution imaging approaches will be combined with genetic, electrophysiological, and behavioral studies to unravel how presynaptic function is linked molecularly to the machinery for quality control to maintain neurotransmission over the lifetime of the brain. Our studies are of fundamental importance for understanding the function and maintenance of synapses and for the development of therapies to combat neurological and neurodegenerative diseases.