Chronic fluoxetine treatment reduces parvalbumin expression and perineuronal nets in gamma-aminobutyric acidergic interneurons of the frontal cortex in adult mice

Mol Brain. 2013 Nov 5:6:43. doi: 10.1186/1756-6606-6-43.


Background: The selective serotonin reuptake inhibitor fluoxetine (FLX) is widely used to treat depression and anxiety disorders, but cellular mechanisms underlying the antidepressant effect of FLX remain largely unknown. The generally accepted effect of chronic FLX treatment is increased adult neurogenesis in the hippocampal dentate gyrus. It was recently demonstrated that FLX treatments can reverse the established neuronal maturation of granule cells in the hippocampal dentate gyrus and of gamma-aminobutyric acidergic (GABAergic) interneurons in the basolateral amygdala. However, it is not clear whether this dematuration effect of FLX occurs in other brain regions. Thus, in this study, we used immunohistological analysis to assess the effect of FLX treatment on GABAergic interneurons in the medial frontal cortex (mFC) and reticular thalamic nucleus (RTN).

Results: Immunofluorescence analysis for perineuronal nets (PNNs), which is a marker of neuronal maturation, and for parvalbumin, calretinin, and somatostatin, which are markers for specific GABAergic interneuron type, showed lower number of parvalbumin-positive (+) cells and PNN+/parvalbumin+ cells in the mFC of FLX-treated mice compared to vehicle-treated mice. However, FLX treatment had no effect on the number of cells expressing calretinin and somatostatin in the mFC. In the RTN, the number of PNN+ cells and parvalbumin+ cells was unaltered by FLX treatments. Furthermore, the number of total GABA+ cells and apoptotic cells in the mFC was similar between vehicle- and FLX-treated mice, suggesting that FLX treatment did not induce cell death in this region. Rather, our findings suggest that the decreased number of parvalbumin+ cells in the mFC was due to a decreased expression of parvalbumin proteins in the interneurons.

Conclusions: This study indicates that FLX decreases the levels of parvalbumin, a mature marker of fast-spiking interneurons, and PNNs in parvalbumin+ interneurons in the mFC, suggesting that FLX treatment induces a dematuration of this type of neurons. Induction of a juvenile-like state in fast-spiking inhibitory interneurons in these regions might be involved in the therapeutic mechanism of this antidepressant drug and/or some of its adverse effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism*
  • Animals
  • Apoptosis / drug effects
  • CA3 Region, Hippocampal / drug effects
  • CA3 Region, Hippocampal / metabolism
  • CA3 Region, Hippocampal / pathology
  • Calbindin 2 / metabolism
  • Cell Count
  • Fluoxetine / administration & dosage
  • Fluoxetine / pharmacology*
  • Frontal Lobe / drug effects
  • Frontal Lobe / metabolism*
  • GABAergic Neurons / metabolism*
  • GABAergic Neurons / pathology
  • Interneurons / drug effects
  • Interneurons / metabolism*
  • Interneurons / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Parvalbumins / metabolism*
  • Somatostatin / metabolism
  • Thalamus / drug effects
  • Thalamus / metabolism
  • Thalamus / pathology
  • gamma-Aminobutyric Acid / metabolism


  • Calbindin 2
  • Parvalbumins
  • Fluoxetine
  • Somatostatin
  • gamma-Aminobutyric Acid