SERT-ainly involved in depression, but when?

The neurotransmitter serotonin is produced by neurons in the raphe nuclei of the brainstem, which send axonal projections broadly to the cerebral cortex, the amygdala, and other brain regions. The modulation of serotonin neurotransmission appears to be involved in both the pathophysiology and the treatment of depression. For example, serotonin-selective reuptake inhibitors (SSRIs), by blocking the reuptake of serotonin into nerve terminals through the serotonin transporter (commonly abbreviated SERT or 5-HTT), reverse the putative deficit of serotonin function in depression. However, the validity of this simple heuristic model is challenged by the variability in the rates of clinical response to pharmacological blockade of the serotonin transporter, suggesting that the exact mechanisms leading to disease and underlying remission are more complex. Here, we briefly review the central role of the serotonin transporter in the normal modulation of serotonin function and the current model of its involvement in the patho-physiology and treatment of depression. We then examine how three reports in this issue of the Journal shed new light on this model by partially refining some of its features and suggesting new areas for investigation. When released from the synaptic vesicles in nerve terminals into the extracellular space, serotonin binds to the numerous types of pre-and postsynaptic serotonin receptors. These receptors in turn activate or repress diverse signal transduction cascades, and thus change the functional status of the targeted neu-rons, while also inducing long-term structural changes through the regulation of gene expression. The availability, and hence signaling potential, of released serotonin is regulated solely through the action of the serotonin transporter. The serotonin transporter captures serotonin molecules and transports them back into the nerve terminal, making them available for recycling into new synaptic vesicles. Consequently, the strength of serotonin activity at serotonin receptors is inversely proportional to the number of functional serotonin transporter molecules present at the presynaptic membrane. SS-RIs and related antidepressant drugs exploit this relationship by blocking the reuptake of serotonin through serotonin transporters, thus increasing serotonin signaling at large. Depending on the brain region and the cellular localization of serotonin transporters , different outcomes may occur. For instance, blocking serotonin transporters in the projection fields of serotonin axons (e.g., in the cerebral cortex or amygdala) increases serotonin levels and signaling at all available serotonin receptors. In contrast, blocking serotonin transporters near serotonin-containing cell bodies (i.e., in the raphe nuclei) leads to increased activation of serotonin 1A (5-HT 1A) autoreceptors, …