Molecular mechanisms of presynaptic membrane recycling, turnover, and transport

脑功能在很大程度上取决于化学突触的神经传递，而突触功能障碍会导致从癫痫、精神分裂症、自闭症到痴呆症等各种疾病。神经递质释放是通过激活区突触囊泡（SVs）的钙触发融合介导的，随后是内吞膜恢复和SV重组。尽管经过数十年的研究，关于突触前内吞作用的机制、外内吞平衡的维持、突触前膜成分的更新以及突触前功能与质量控制耦合的机制等基本问题仍未得到解答。在这个项目中，我们的目标是阐明突触前外吞作用通过自噬-溶酶体途径调节膜周转和运输的分子机制。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、电生理学和行为研究相结合，揭示突触前功能如何在分子上与质量控制机制联系起来，以维持大脑生命周期内的神经传递。我们的研究对于理解突触的功能和维持以及开发对抗神经和神经退行性疾病的疗法具有重要意义。

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.