Serotonin synthesis, release and reuptake in terminals: a mathematical model

Abstract

Background: Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system.

Methods: We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data.

Results: We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to experimental data. Finally, we study how the properties of the the serotonin transporter and the autoreceptors give rise to the time courses of extracellular serotonin in various projection regions after a dose of fluoxetine.

Conclusions: Serotonergic systems must respond robustly to important biological signals, while at the same time maintaining homeostasis in the face of normal biological fluctuations in inputs, expression levels, and firing rates. This is accomplished through the cooperative effect of many different homeostatic mechanisms including special properties of the serotonin transporters and the serotonin autoreceptors. Many difficult questions remain in order to fully understand how serotonin biochemistry affects serotonin electrophysiology and vice versa, and how both are changed in the presence of selective serotonin reuptake inhibitors. Mathematical models are useful tools for investigating some of these questions.

Figure 1

Steady state concentrations and fluxes. The figure shows the reactions in the model. The rectangular boxes indicate substrates and blue ellipses contain the acronyms of enzymes, transporters, and autoreceptors; steady state values in the model are indicated. Full names of the substrates are given in Table 1. Names of enzymes and transporters are as follows: Trpin, neutral amino acid transporter; DRR, dihydrobiopterin reductase; TPH, tryptophan hydroxylase; AADC, aromatic amino acid decarboxylase; MAT, vesicular monoamine transporter; SERT, 5-HT reuptake transporter; auto, 5-HT autoreceptors; MAO monoamine oxidase; ALDH, aldehyde dehydrogenase. Removal means uptake by capillaries or glial cells or diffusion out of the system.

Figure 2

The effect of meals on brain DA and 5-HT. Panel A shows the blood concentration over a 24 hour period of either tyrosine or tryptophan due to three meals at 7 am, 12 pm and 6 pm. Panel B shows the tyrosine and tryptophan concentrations in dopaminergic and serotonergic synaptic terminals. Panel C shows the velocities of the TH and TPH reactions over the same 24 hour period. Panel D shows the extracellular DA and 5-HT concentrations. The vesicular stores of DA and 5-HT (not shown) vary like the extracellular concentrations in Panel D. All calculations for DA were done using the mathematical model described in [41] and the calculations for 5-HT were done using the mathematical model in this paper.

Figure 3

Release and reuptake. The time course of extracellular 5-HT is shown for a model experiment where the neuron was stimulated for 1/5 of a second (blue curve). In the presence of fluoxetine, the time course goes slightly higher and the decay time back to baseline doubles (green curve). We modeled the presence of fluoxetine by blocking half the SERTs. The curves are very similar to those in Figure six of [46].

Figure 4

Homeostatic effects of the autoreceptors. Panel A shows hows extracellular 5-HT (e5ht) changes as the firing rate of the neuron varies above and below normal both with and without the autoreceptors. Panel B shows how extracellular 5-HT changes with the expression level of the SERTs both with and without the autoreceptors. s/s and l/l indicate the activities of the corresponding genotypes. Panel C shows how extracellular 5-HT changes with the activity level of TPH both with and without the autoreceptors. The activities of the R441 H and P449R polymorphims are indicated. In all cases, the autoreceptors reduce the effect of changes in firing rate and polymorphisms on extracellular 5-HT.

Figure 5

Effects of 5-HT1A agonists and fluoxetine. Panel A shows the change in extracellular 5-HT in the hippocampus and the frontal cortex computed by the model after a 5-HT1A agonist is given. The curves are similar to those in [108]. Panel B shows model computations of the extracellular concentrations of 5-HT in the hippocampus and the frontal cortex after a dose of an SSRI (fluoxetine or paroxetine); the solid curves are wild type and the dashed curves are 5-HT1B knockouts. These curves should be compared to Figure one (10 mg/kg dose) in [106] and Figure one (a, b, c, d) in [109]. For discussion, see the text.