Identification of the cortical neurons that mediate antidepressant responses

Cell. 2012 May 25;149(5):1152-63. doi: 10.1016/j.cell.2012.03.038.


Our understanding of current treatments for depression, and the development of more specific therapies, is limited by the complexity of the circuits controlling mood and the distributed actions of antidepressants. Although the therapeutic efficacy of serotonin-specific reuptake inhibitors (SSRIs) is correlated with increases in cortical activity, the cell types crucial for their action remain unknown. Here we employ bacTRAP translational profiling to show that layer 5 corticostriatal pyramidal cells expressing p11 (S100a10) are strongly and specifically responsive to chronic antidepressant treatment. This response requires p11 and includes the specific induction of Htr4 expression. Cortex-specific deletion of p11 abolishes behavioral responses to SSRIs, but does not lead to increased depression-like behaviors. Our data identify corticostriatal projection neurons as critical for the response to antidepressants, and suggest that the regulation of serotonergic tone in this single cell type plays a pivotal role in antidepressant therapy.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antidepressive Agents / metabolism*
  • Antidepressive Agents / pharmacology
  • Depression / drug therapy*
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • Neurons / cytology*
  • Prefrontal Cortex / cytology*
  • Prefrontal Cortex / metabolism
  • Pyramidal Cells / metabolism
  • S100 Proteins / genetics
  • S100 Proteins / metabolism
  • Selective Serotonin Reuptake Inhibitors / metabolism*
  • Selective Serotonin Reuptake Inhibitors / pharmacology


  • Antidepressive Agents
  • S100 Proteins
  • Serotonin Uptake Inhibitors