Fig 1.
DA spiking patterns and transmission influence cognition and behavior.
DA terminal co-localized with a fronto-striatal connection and the two modes of spike-dependent DA release: tonic and phasic spiking. Synaptic spillover facilitates volume transmission. Tonic spiking resulting in tonic DA concentration is primarily associated with volume transmission relevant for pre-synaptic control and, on a functional level, with a motivational drive. Phasic DA acts also pre-synaptically via volume transmission and might be involved in terminating phasic spiking signals. However, phasic spiking, i.e. bursts and pauses, and phasic DA are functionally more relevant for learning. Increased and decreased prevalence of synaptic transmission between DA neuron terminals and specific target post-synaptic neurons contribute to post-synaptic cell excitability. In addition, synaptic spillover following burst firing can increase extra-synaptic DA concentration and modulate fronto-striatal loop connections. Depending on how localized this signal is, the definition of volume transmission may not apply.
Fig 2.
Difference between point source model, synaptic model and non-synaptic model.
Fig 3.
Single DA release event from synaptic terminal.
For all plots the initial baseline concentration was 4nM except in B & D where the inital baseline concentration was 50nM. A-D: Release of 3000 DA molecules from synaptic terminal. White isolines indicate the concentration of 10, 100 and 1000nM. All color scales represent concentration in μM. DA quickly escapes the synaptic cleft in scenarios without uptake (A & B) and also with volume (homogeneous) uptake (C & D). E: Detail of plot C with additional isolines of 10, 100 and 1000nM for simulations with a combination of volume and surface uptake (inhomogeneous uptake). White isolines refer to the simulation with volume uptake only. Gray and black isolines refer to the simulation where surface uptake was five and one-hundred times elevated, resp. Neither homogeneous uptake nor uptake strongly pronounced at the pre-synaptic terminal can prevent synaptic spillover. F: Concentration difference between simulations of homogeneous (white) and inhomogeneous uptake with five (gray) and one-hundred (black) times elevated uptake at the pre-synaptic terminal. G: Fast D2 receptor binding at different distances from release site. Comparable receptor binding occurs at distances up to 0.5μm. The blue and yellow graph are equivalent. D2R binding at half the distance of neighboring terminals (2.0μm) is still profound but negligible at 4.0μM. Differences between a synaptic (solid line) and a non-synaptic terminal (dashed line) could not be confirmed. H: Slow D2 receptor binding at different distances from release site for a synaptic (solid line) and a non-synaptic terminal (dashed line). Elevated receptor binding occurs at a distance of 0.1μm, (i.e. inside the synapse for the synaptic terminal with radius = 0.15μm), but not at distances beyond 0.2μm. D2R binding beyond half the distance of neighboring terminals (2.0μm) is small and negligible at 4.0μm.
Fig 4.
Multiple DA release events from synaptic terminal.
A: Simulated concentration [μM] with 3000 molecules released per event. B: Associated equilibrium receptor binding (Michaelis-Menten kinetics). C: Associated slow receptor binding. Percentage of binding increases with each release event inside and close to release site. At 2μm distance from the synapse center increments become insignificantly small. D: Associated fast receptor binding. Again, at 2μm distance from the synapse center receptor binding becomes insignificantly low.
Fig 5.
Volume-averaged DA concentration for the three different simulation settings. Fast oscillations occur in the DSS and SRS, while low frequency oscillations occur in the UIS. DSS: default setting simulation, SRS: stimulated release simulation, UIS: uptake inhibition simulation.
Fig 6.
DA concentration and D2R binding characteristics for four randomly chosen finite elements containing a synaptic terminal. Depicted at the bottom is DA concentration within the finite element of the tonic model, i.e. extra-synaptic DA concentration within a radius of ~ 0.8μM from the terminal. Large concentration peaks indicate DA release from this synapse, while smaller peaks are caused by DA release from neighboring terminals. As the same amount of DA molecules is released every time, peak concentration in larger volumes (coarser resolutions) are smaller. The upper (dotted lines) and middle graphs (solid lines) illustrate slow D2R binding in a short time window for the SRS in synaptic (dotted) and peri-synaptic (solid) space.
Fig 7.
A) Tonic (large-scale) and synaptic (small-scale) model. The tonic model contains more than 13000 finite elements that are associated with synaptic and non-synaptic terminals. For non-synaptic terminals the whole vesicle content is released into the respective finite element, while synaptic terminals refer to the synaptic model. B) DA diffusion from a synaptic terminal. Concentration 0.1 ms after release.