Serotonin-specific reuptake inhibitors (SSRIs) are used to treat depressive disorders, which affect ∼10% of the population. Improving treatment requires a better understanding of the molecular pathways affected by these agents in different brain-cell populations. Addressing this issue has been difficult owing to the interconnectivity and complexity of brain-cell populations. Schmidt and colleagues overcame this challenge by using a transgenic mouse model involving a bacTRAP translational profiling approach to investigate the role of the p11 protein in responses to SSRIs. p11 is known to maintain serotonin receptors at the cell surface and to mediate antidepressant responses; some studies indicate that its expression is decreased in the brains of those with depression. The researchers tracked cells that were actively translating p11 protein and characterised their response to SSRIs. On treating mice with an SSRI, p11 expression was upregulated in a specific subset of cells in the frontal cortex, the layer 5 corticostriatal projection neurons, and resulted in induced expression of Htr4, encoding a serotonin receptor. Genetic ablation of p11 in this cell type prevented the upregulation of Htr4 and reduced the efficacy of SSRI treatment in mice. These data identify the cell type that is important in mediating the response to SSRIs, and provide unique mechanistic insight that might help to refine therapeutics for depression.

E. F.
J. L.
B. G.
S. B.
Identification of the cortical neurons that mediate antidepressant responses

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