Effects of Presynaptic Calcium Stores on Short-Term Synaptic Plasticity

Abstract

In reconstructions of hippocampal neuropil, Smooth Endoplasmic Reticulum (SER) appears in a majority of the presynaptic terminals. In the presence of ongoing electrical activity, Inositol Triphosphate Receptors (IP3Rs) on the SER initiate a positive feedback loop that can lead to release of calcium from the SER via an IP3-mediated pathway. We investigated how the presence of this additional source of calcium in addition to the Voltage Dependent Calcium Channels (VDCCs) can regulate synaptic transmission. We carried out 3D Monte Carlo simulations of the molecular interactions that govern transmitter release in a 1) Canonical CA3-CA1 synapse 2) Synapse reconstructed from serial section Transmission Electron Microscope images. The relatively simple geometry of CA3-CA1 synapses allows activity-dependent local calcium at the active zone and the related transmitter release profiles to be quantitatively analyzed. In paired-pulse stimulation, the presence of molecular pathways that regulate the calcium stores increased the calcium buffering capacity of the synapse, which decreased the initial release probability and enhanced paired-pulse facilitation. In contrast, a high-frequency stimulus could trigger the activation of presynaptic Metabotropic Glutamate Receptors (mGluRs) leading to IP3 production and ultimately to release of calcium from the SER. IP3Rs operated at a much slower time scale, on the order of seconds compared to the millisecond timescale of the VDCCs. This led to an increase in the basal level of intracellular calcium and enhanced transmitter release rates. We further explored the functional implications of the range of SER geometries observed in the synaptic ultrastructure and the effect of different arrangements between IP3Rs and VDCCs on synaptic plasticity. The synaptic ultrastructure precisely orchestrated the degree of facilitation and depression and the existence of presynaptic calcium stores provided the synapse with an additional intrinsic time scale that could be regulated by activity.