Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine

• Cyclin D2 KO mice have markedly reduced hippocampal neurogenesis.
• These mice do not show depressive symptoms, such as increased immobility.
• They show stressed-evoked increase of immobility in forced swim test.
• This increase is reduced by chronic fluoxetine without any changes in neurogenesis.
• Efficiency of antidepressant fluoxetine does not depend on adult brain neurogenesis.

The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine. After unpredictable chronic mild stress, mutant mice showed depression-like behavior in forced swim test, which was eliminated with chronic fluoxetine treatment, despite its lack of impact on adult hippocampal neurogenesis in cD2 KO mice. Our results suggest that new neurons are not indispensable for the action of antidepressants such as fluoxetine. Using forced swim test and tail suspension test, we also did not observe depression-like behavior in control cD2 KO mice, which argues against the link between decreased adult brain neurogenesis and major depression.