Increased Extrasynaptic Glutamate Escape in Stochastically Shaped Probabilistic Synaptic Environment

Excitatory synapses in the brain are often surrounded by nanoscopic astroglial processes that express high-affinity glutamate transporters at a high surface density. This ensures that the bulk of glutamate leaving the synaptic cleft is taken up for its subsequent metabolic conversion and replenishment in neurons. Furthermore, variations in the astroglial coverage of synapses can thus determine to what extent glutamate released into the synaptic cleft could activate its receptors outside the cleft. The biophysical determinants of extrasynaptic glutamate actions are complex because they involve a competition between transporters and target receptors of glutamate in the tortuous space of synaptic environment. To understand key spatiotemporal relationships between the extrasynaptic landscapes of bound and free glutamate, we explored a detailed Monte Carlo model for its release, diffusion, and uptake. We implemented a novel representation of brain neuropil in silico as a space filled with randomly scattered, overlapping spheres (spheroids) of distributed size. The parameters of perisynaptic space, astroglial presence, and glutamate transport were constrained by the empirical data obtained for the ‘average’ environment of common cortical synapses. Our simulations provide a glimpse of the perisynaptic concentration landscapes of free and transporter-bound glutamate relationship, suggesting a significant tail of space-average free glutamate within 3 ms post-release.