Molecular Mechanisms That Control the Quality of Synaptic Vesicle Recycling

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Neuronal communication underpins all cognitive and physical activities (i.e., movement, perception, learning, and memory). High quality communication is essential to maintain organism homeostasis and disruptions lead to severe consequences. Synaptic vesicles (SVs) store and release neurotransmitters and serve as morphological counterparts of the neurotransmitter quanta. Thus, both morphology and function of SVs have significant implications in the quantal information transmitted from one neuron to another. The activity of SVs is highly dynamic. Upon arrival of Ca2+ signals, SVs fuse with the plasma membrane and release their neurotransmitter content through exocytosis. After exocytosis, SVs are incorporated into the plasma membrane and then must be retrieved into newly formed vesicles by SV endocytosis. This SV recycling is one of the best-orchestrated biological processes known, and at the same time, many of the intricate mechanisms that govern recycling remain unknown. It is imperative to gain a grasp of the mechanisms as scientific research recognizes that defects in vesicle property creates deficits in synaptic transmission, a common failing that underlies various forms of neurological and psychiatric disorders. The long-term goal of our work is to elucidate the fundamental mechanisms underlying effective neuronal communication by ensuring quality of SVs. AP180, a 180-kD adapter protein isolated from brain tissues, has been identified as a critical presynaptic protein and major component of clathrin-coated vesicles. AP180 has been implicated in human psychiatric and neurodegenerative disorders including schizophrenia and Alzheimer’s disease. Genetic data demonstrate that AP180 has crucial roles in controlling the morphology and protein composition of SVs and its disruption causes synaptic defects in worms, fruit flies, and mice. Using the nematode C. elegans as a model system, we plan to investigate and firmly establish the role of AP180 in maintaining both morphological and functional integrity of SVs in this project. We will design and employ state-of-the-art genetics, cell biology, biochemistry, and electrophysiological techniques to dissect the role of AP180. The proposal has three specific aims and addresses 1) the central role of AP180 in a two-step mechanism for SV recycling, 2) the intriguing activity- dependent regulation of AP180 dynamics at the synapse, and 3) the AP180-dependent mechanism that controls the size of SVs. We have built our hypotheses on solid knowledge base; our incisive methodologies have strong prospects to yield deep insights into SV recycling. The knowledge gained on the function, dynamics, and specificity of AP180 has broad ramifications in synaptic activity and brain function. Together, our studies hold promise to push boundaries of the current knowledge of synaptic transmission and broaden horizons with a strong potential to unravel the neurological intricacies and invent solutions for neurological disorders.