Chronic fluoxetine treatment alters the structure, connectivity and plasticity of cortical interneurons

Int J Neuropsychopharmacol. 2014 Oct;17(10):1635-46. doi: 10.1017/S1461145714000406. Epub 2014 Apr 30.


Novel hypotheses suggest that antidepressants, such as the selective serotonin reuptake inhibitor fluoxetine, induce neuronal structural plasticity, resembling that of the juvenile brain, although the underlying mechanisms of this reopening of the critical periods still remain unclear. However, recent studies suggest that inhibitory networks play an important role in this structural plasticity induced by fluoxetine. For this reason we have analysed the effects of a chronic fluoxetine treatment in the hippocampus and medial prefrontal cortex (mPFC) of transgenic mice displaying eGFP labelled interneurons. We have found an increase in the expression of molecules related to critical period plasticity, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), GAD67/65 and synaptophysin, as well as a reduction in the number of parvalbumin expressing interneurons surrounded by perineuronal nets. We have also described a trend towards decrease in the perisomatic inhibitory puncta on pyramidal neurons in the mPFC and an increase in the density of inhibitory puncta on eGFP interneurons. Finally, we have found that chronic fluoxetine treatment affects the structure of interneurons in the mPFC, increasing their dendritic spine density. The present study provides evidence indicating that fluoxetine promotes structural changes in the inhibitory neurons of the adult cerebral cortex, probably through alterations in plasticity-related molecules of neurons or the extracellular matrix surrounding them, which are present in interneurons and are known to be crucial for the development of the critical periods of plasticity in the juvenile brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents, Second-Generation / pharmacology*
  • Cell Count
  • Cerebral Cortex / cytology*
  • Dendritic Spines / drug effects
  • Fluoxetine / pharmacology*
  • Gene Expression Regulation / drug effects
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Interneurons / cytology
  • Interneurons / drug effects*
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Net / drug effects*
  • Nerve Tissue Proteins / metabolism
  • Neural Cell Adhesion Molecule L1 / metabolism
  • Neuronal Plasticity / drug effects*
  • Parvalbumins / genetics
  • Parvalbumins / metabolism
  • Sialic Acids / metabolism
  • Time Factors
  • Vesicular Glutamate Transport Protein 1 / metabolism


  • Antidepressive Agents, Second-Generation
  • Nerve Tissue Proteins
  • Neural Cell Adhesion Molecule L1
  • Parvalbumins
  • Sialic Acids
  • Vesicular Glutamate Transport Protein 1
  • polysialyl neural cell adhesion molecule
  • Fluoxetine
  • Green Fluorescent Proteins
  • Glutamate Decarboxylase