Modelling Vesicular Release at Hippocampal Synapses

We study local calcium dynamics leading to a vesicle fusion in a stochastic, and spatially explicit, biophysical model of the CA3-CA1 presynaptic bouton. The kinetic model for vesicle release has two calcium sensors, a sensor for fast synchronous release that lasts a few tens of milliseconds and a separate sensor for slow asynchronous release that lasts a few hundred milliseconds. A wide range of data can be accounted for consistently only when a refractory period lasting a few milliseconds between releases is included. The inclusion of a second sensor for asynchronous release with a slow unbinding site, and thereby a long memory, affects short-term plasticity by facilitating release. Our simulations also reveal a third time scale of vesicle release that is correlated with the stimulus and is distinct from the fast and the slow releases. In these detailed Monte Carlo simulations all three time scales of vesicle release are insensitive to the spatial details of the synaptic ultrastructure. Furthermore, our simulations allow us to identify features of synaptic transmission that are universal and those that are modulated by structure.Author Summary: Chemical synaptic transmission in neurons takes place when a neurotransmitter released from a nerve terminal of the presynaptic neuron signals to the postsynaptic neuron that an event has occurred. The goal of our research was to model the release at a type of synapse found in the hippocampus, a part of the brain that is involved with learning and memory. The synapse model was simulated in a computer that kept track of all of the important molecules in the nerve terminal. The model led to a better understanding of the extant experimental data including exact conditions that lead to the release of a single packet of neurotransmitter. According to our model, the release of more than one packet can be triggered by a single presynaptic event but the packets are released one at a time. Furthermore, we uncovered the mechanisms underlying an extremely fast form of release that had not been previously studied. The model made predictions for other properties of the synapse that can be tested experimentally. A better understanding of how the normal synapses in the hippocampus work will help us to better understand what goes wrong with synapses in mental disorders such as depression and schizophrenia.