Presynaptic calcium dynamics during short-term plasticity

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Communication between neurons occurs via synaptic contacts, information is coded by the temporal properties and the quantity of neurotransmitter release. Neurotramsitter release is tightly regulated and controlled by changes in presynaptic calcium concentration. Presynaptic activity leads to the activation of various types of calcium channels and hence calcium entry to the terminal from extracellular sources, in addition calcium can also be released from intracellular pools in an activity-dependent fashion. Dynamic changes in calcium concentration endow the terminal with the ability to operate at a wide variety of release modes. It has been long believed that that these various modes of presynaptic operation can be explained by changes in calcium concentration. In contrast, in the current proposal we propose to test the following hypothesis: Calcium entry via different types of voltage gated calcium channels regulate and control distinct physiological properties of neurotransmitter release. We propose that the properties, the density, and the spatial distribution of specific voltage-gated calcium channels (VGCCs) in presynaptic terminals allows targeted calcium influx to initiate the different modes of neurotransmitter release under specific patterns of activity.  In order to test this hypothesis; the experimental plan is divided into three objectives: 1. How does the distribution of VGCCs differs between active zones in the same presynaptic terminal? What role do different types of VGCCs play in neurotransmitter release? 2. How does repetitive activity modulate calcium microdomains to shape short-term facilitation of neurotransmitter release? 3. How and under what circumstances are calcium elevations globalized? We will use pharmacological approaches to determine the contribution of various types of VGCCs to synaptic interactions during various levels of activity, while properties of different release mechanism will be evaluated with quantal analysis. We will use RAMP microscopy to determine the size and distribution of calcium microdomains and how they change during increased synaptic activity. And finally we will use electron microscopy to determine the spatial distribution of various types of VGCCs in relation to the active zones in single presynaptic terminals. Altogether these experiments will provide a complex and comprehensive picture on how calcium entry during neuronal activity via different types of VGCCs shape neurotransmitter release.