Serotonin synapse modelling. (A) Processes involved in measuring free serotonin levels by fast cyclic voltammetry. In this particular simulation only the change in free 5-HT, but no postsynaptic activation level is measured. The simulation setup forces high frequency firing on the presynaptic nerve endings and allows calibration of the different presynaptic parameters that regulate the coupling between presynaptic autoreceptor activation, firing history and subsequent neurotransmitter release. Some parameters, such as 5-HT release and half-life are constrained by biological limits. (B) Correspondence between model outcomes and experimentally reported values in the mouse substantia nigra under forced firing frequencies. The model parameters of the serotonergic synapse are adjusted to show a good correlation with the experimental data. This particular calibration is for the situation where the extrasynaptic concentration equals the intrasynaptic free level of 5-HT. (C) Correspondence between model outcomes and experimentally reported values  in the mouse dorsal raphe under forced firing frequencies where a specified number of pulses was given at 30 Hz. The model parameters of the serotonergic synapse are adjusted to show a good correlation with the experimental data. (D) Global difference between simulated and clinically measured data. Similar curve fittings to (B) are done for other situations (from 1 to 10 times the measured extrasynaptic levels). Because the in vivo serotonergic firing frequency is around 1 Hz, we took great care to fit the low end of the frequency datapoints.