Epistasis among presynaptic serotonergic system components.

Epistatic interactions among regulatory components of the serotonin (5-HT) neurotransmitter system may be an important aspect of 5-HT function. Because 5-HT dysregulation is associated with several common psychiatric disorders, the potential for epistasis among genetic variants in the 5-HT transporter (SERT), 5-HT1B terminal autoreceptor and the 5-HT1A somatodendritic autoreceptor should be examined. In this study, output from a dynamic minimal model of 5-HT function was compared to empirical results in the literature. Parameters representing extracellular 5-HT clearance rates (SERT), 5-HT release levels (5-HT1B) and inhibitory thresholds (the amount of extracellular 5-HT above which cell firing is inhibited, an indication of 5-HT1A autoreceptor sensitivity) were varied to simulate genetic deletion (i.e. knockout) of each component singly, and in combination. Simulated knockout effects on extracellular 5-HT level and presynaptic neural firing rates were in the same direction and of similar relative magnitude as studies in the literature. Epistasis among presynaptic components appears to be important in the 5-HT system's regulation of extracellular 5-HT levels, but not of firing rates.