Changes in the effectiveness of synapses underlie the ability of neuronal networks to store and retrieve information, the cellular level representation of learning and memory. One form of synaptic plasticity is facilitation, a phenomenon by which a synapse becomes transiently more effective following repeated use. The classical interpretation of facilitation has been that nerve repetitive stimulation increases Ca2+ concentration at presynaptic release sites, which in turn increases the probability of each site to release a vesicle. However, more recently it became clear that this explanation is incomplete. We have recently shown that changes in the number of synaptic vesicles properly activated to be released (the releasable pool of vesicles) also contribute to facilitation. We propose to investigate quantitatively how the regulation of the releasable pool of vesicles by presynaptic machinery affects facilitation. Synapsins, a family of neuron specific phosphoproteins, regulate binding of vesicles to actin filaments and thereby control availability of vesicles to become releasable. Consistently with the proposed role of the releasable vesicle pool in facilitation, we have recently demonstrated that transmitter release and facilitation are regulated by synapsin in a Ca2+-dependent manner. In the present application we propose to investigate quantitatively how synapsin regulates presynaptic vesicle cycling, recruitment of vesicles in the releasable pool, and thereby different forms of facilitation. Our proposal relies on the combination of experimentation and modeling, since presynaptic terminals are not easily accessible for experimental manipulations, and all the vesicle pools cannot be measured precisely. Our overall approach is to investigate regulation of vesicle pools by synapsin, to simulate quantitatively the dynamics of vesicle pools, and to verify modeling by its ability to account for different facilitation forms and their regulation by synapsin. All the developed computational algorithms will be available to other scholars.
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