Quantifying the synaptic Ca2+-binding kinetics of Synaptotagmin-1, the Ca2+ sensor for transmitter release in the forebrain

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Central nervous system neurons communicate via Ca2+-triggered release of neurotransmitters from presynaptic terminals. Upon depolarization of a terminal voltage-gated Ca2+ channels open and the inflowing Ca2+ builds a steep, short lasting concentration gradient around the mouth of the open channel that rapidly diminishes with increasing distance from the channel. Ca2+ binds to specialized Ca2+ sensor proteins (Synaptotagmins, Syt), thereby, triggering the fusion of neurotransmitter filled vesicles with the plasma membrane of the presynaptic active zone and the subsequent release of the transmitter. Due to the steepness and short duration of the Ca2+ gradient a chemical equilibrium is never established in this process. This makes the intracellular Ca2+-binding kinetics of the release sensor (as opposed by its affinity at equilibrium) central in the control of speed, reliability and modulation capability of release. Thus, in order to derive a quantitative understanding of synaptic information transfer but also of its modulation via synaptic plasticity it is required to know the intracellular Ca2+-binding kinetics of the release sensor. Two Syt isoforms, Syt1 and Syt2, are the main Ca2+ sensors triggering fast transmitter release in the brain; however, only Ca2+-binding to Syt2, the dominant isoform in the hindbrain has been studied in detail in synapses. Syt1, the dominating sensor in the forebrain, is thought to behave differently but detailed quantitative data of its synaptic Ca2+-binding kinetics are missing. Resolving this major uncertainty for understanding synaptic information flow and its regulation in forebrain regions like the neocortex is topic of the present proposal.