The therapeutic efficacy of serotonin-specific reuptake inhibitor antidepressants (SSRIs) is correlated with increases in cortical activity but the cell types involved in this action remain unknown. The authors of this study show that layer 5 corticostriatal pyramidal cells expressing p11 (a member of the S100 family of calcium effector proteins) are strongly and specifically responsive to chronic treatment with the SSRI antidepressant fluoxetine. This response requires p11 and includes the specific induction of serotonin receptor subtype 4 expression. Cortex-specific deletion of p11 abolishes behavioral responses to SSRIs, but does not lead to increased depression-like behaviors. The study identified corticostriatal projection neurons as critical for the response to antidepressants, and suggested that the regulation of serotonergic tone in this single cell type plays a pivotal role in antidepressant therapy. The authors suggest that development of drugs that specifically target the activity of corticostriatal neurons may result in improved therapies for depression.

Schmidt EF, Warner-Schmidt JL, Otopalik BG, Pickett SB, Greengard P, Heintz N: Identification of the Cortical Neurons that Mediate Antidepressant Responses. Cell 149 (5): 1152-1163 (2012).

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