Synaptic Vesicle Trafficking in Hippocampal Synapses

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Revised Abstract Section Brain function depends critically on the normal operation of synapses and their capacity for modification. An understanding the basic properties of synaptic transmission and plasticity is necessary for illuminating the mechanisms of synaptic dysfunction in disease. In recent years, substantial progress has been made in understanding the molecular mechanisms of neurotransmitter release through exocytosis of synaptic vesicles, as well as on recapture of the spent vesicle through endocytosis. But relatively little is known about the important steps between endocytosis and subsequent reuse of vesicles, as well as on how vesicles are organized within the synaptic terminal. The properties of the different pools of vesicle and the movement of vesicles between different pools are major determinants of the efficacy of synaptic transmission during sustained activity. Importantly, synaptic vesicle pools and their trafficking are dynamically modulated during development, and in some forms of plasticity. The overall objective of this research program is to determine the mechanisms in recycling and mobilization of synaptic vesicles and the mechanisms involved in modulation of vesicle pools. In particular, we are interested in dissecting out these mechanisms in a class of synapses that release GABA as neurotransmitter. Much of the work on vesicle pools and trafficking to date has involved excitatory synapses that release glutamate, with the implicit assumption that the mechanisms are likely to be shared across different types of synapses. But there are clear indications of important differences between glutamatergic and GABAergic synapses. Prompted by our own recent findings, we will investigate the mechanisms in synaptic vesicle trafficking in GABAergic synapses and its regulation by activity. We will combine sophisticated real-time microscopy of individual presynaptic terminals with electrophysiology, molecular biology and electron microscopy to investigate presynaptic function, guided by the following aims: (i) To test the hypothesis that activity positively regulates multiple aspects of presynaptic function at inhibitory synapses in the hippocampus, and (ii) To investigate the mechanisms underlying activity-dependent changes in evoked transmitter release and the short-term dynamics of GABAergic synapses. These experiments will elucidate fundamental presynaptic mechanisms of vesicle traffic in GABAergic synapses and how they are altered by activity.