Non-linear relationship between SERT expression and frequency sensitivity of 5-HT signals

Variation in expression and function of the human 5-hydroxytryptamine (5-HT, serotonin) transporter (SERT) is associated with psychiatric disturbances [1,2]. Such associations remain controversial however, and the underlying neurobiology is not understood. One point of discordance is that whilst SERT levels seem to inversely correlate with brain 5-HT levels, the relationship between SERT levels (or expression-modifying polymorphisms) and psychiatric phenotype appears to be more complex; i.e. both high and low SERT expressing alleles associate with detrimental psychiatric phenotypes. How SERT levels impose changes in brain 5-HT levels to modulate psychiatric vulnerability is an important question for understanding the behavioural consequences of serotonergic dysfunction. However, better understanding of how SERT regulates 5-HT is needed since previous studies assayed brain 5-HT on a timescale too low to resolve the dynamic fluctuations in extracellular levels that are predicted by reported patterns of activity in vivo [3,4].