Functional architecture and structural dynamics at the presynaptic Active Zone

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Presynapses transduce action potentials into neurotransmitter release by means of Ca2+ mediated synaptic vesicle (SV) fusion, at millisecond speed and at sustained rates of hundreds of hertz, demanding efficient Ca2+ secretion coupling, rapid replenishment and efficient clearance of SV material. The active zone (AZ), a protein-rich presynaptic structure, organizes release, replenishment and recycling of SVs, and aligns the pre- with the postsynapse. Our cutting-edge technology, termed “flash-and-freeze”, overcomes previous limits in temporal resolution and allows us now to construct time-lapse movies of presynaptic structural dynamics at unprecedented spatiotemporal resolution based on electron and super resolution light microscopy analyses. Studying the presynapse with such methods will allow us to address 1) how AZ modules define SV fusion sites and trans-synaptic organization; 2) determine the post-fusion dynamics and recycling of SV proteins; and 3) examine the nature and mechanism of ultrafast post-fusion SV replenishment to the AZ. By linking molecular, functional and structural dynamics between AZ and SVs following fusion, we will gain unprecedented mechanistic insights into presynapse function, a crucial step in ultimately reconstituting synaptic function by design principles.