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How Serotonin Reuptake Inhibitors Work: Understanding More Fundamental Mechanisms of Action

By stimulating microRNA miR-16 in the midline serotonergic raphe, fluoxetine initiates signaling cascades that lead to hippocampal neurogenesis.

Several lines of evidence suggest that in adults, antidepressant therapies enhance neurogenesis in the hippocampus, but how this process occurs has been unclear. These researchers studied the effects of fluoxetine in mice and in humans. They worked out several pathways that begin with the stimulation by fluoxetine of the microRNA miR-16 in serotonergic neurons in raphe and ultimately result in hippocampal neurogenesis.

In a series of experiments in mice, fluoxetine activated raphe miR-16, which decreased raphe levels of the serotonin reuptake transporter (SERT). In turn, these events directly caused brain-derived neurotropic factor (BDNF) and two other signaling molecules to act on the hippocampus. Indirectly, the same events resulted in release of another protein from the raphe nuclei, S100β, which in turn stimulated the locus coeruleus to induce SERT and secrete serotonin. Both the direct and indirect pathways caused decreases in hippocampal miR-16, which sequentially led to increases in both hippocampal SERT and the bcl-2 protein (which promotes neurotrophic function), which in turn stimulated neurogenesis. In nine patients with major depression, 12-week fluoxetine treatment increased levels of the three signaling molecules in cerebrospinal fluid. The interventions were accompanied by improvements in several mouse models of depression, as well as in the patients. See accompanying figure.

Comment: These findings draw together several seemingly unconnected lines of research. The authors identify miR-16 as a "missing link" between serotonin reuptake inhibitor treatment and hippocampal neurogenesis and as a "micromanager" of the intervening changes in the raphe nucleus, locus coeruleus, serotonin receptor transporter, serotonin secretion, and hippocampal neurogenesis. The processes appear to work through the cooperative and integrated activities of several signaling molecules. Further clarification of these pathways may help refine therapeutic strategies for depressive disorders.

— Joel Yager, MD

Published in Journal Watch Psychiatry January 13, 2012

Citation(s):

Launay JM et al. Raphe-mediated signals control the hippocampal response to SRI antidepressants via miR-16. Translat Psychiatry 2011 Nov 22; 1:e56. (http://dx.doi.org/10.1038/tp.2011.54)

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• How Serotonin Reuptake Inhibitors Work: Understanding More Fundamental Mechanisms of Action
  R G Sagar, 7 Feb 2012 12:18 PM EST
  Specialty: Unspecified
  Will neurogenesis stop it shrinking?

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