Molecular mechanisms of presynaptic membrane recycling, turnover, and transport

点击翻译按钮获取中文摘要

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.