Decoding Depression Circuits

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Science  29 Jun 2012:
Vol. 336, Issue 6089, pp. 1620-1621
DOI: 10.1126/science.336.6089.1620-d

Fluoxetine is a widely prescribed antidepressant that acts as a selective serotonin reuptake inhibitor. Schmidt et al. define a particular set of neurons in the mouse brain that can mediate the effects of this drug. They focused on a set of neurons in the cerebral cortex that extend to the striatum and express the adapter protein p11 (encoded by the S100a10 gene). p11 is known to stabilize the expression of serotonin receptors at the cell surface, and the loss of p11 is associated with depressive behaviors. The authors used a translational profiling method to monitor a specific set of neurons in the cerebral cortex that express p11 and found that they specifically responded to fluoxetine. Depletion of p11 in the cortex showed that these neurons were required for the behavioral effects of the drug. Thus, changes in signaling through serotonin receptors in p11-expressing cells appear to account for the beneficial effect of fluoxetine. However, depletion of p11 was not sufficient to cause depression-like behavior. Thus, in this case, as might be expected for complex disorders such as depression, the cell types that mediate the therapeutic response apparently do not represent the anatomical location of the original genesis of the disease.

Cell 149, 1152 (2012).

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