A complex relation between levels of adult hippocampal neurogenesis and expression of the immature neuron marker doublecortin

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule beta-arrestin-2 (beta-Arr2) is required for the antidepressant-like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and survival of adult-born granule cells are absent in the beta-Arr2 knockout (KO) mice. To our surprise, fluoxetine induced a dramatic upregulation of the number of doublecortin (DCX)-expressing cells in the beta-Arr2 KO mice, indicating that this marker can be increased even though AHN is not. We discovered two other conditions where a complex relationship occurs between the number of DCX-expressing cells compared to levels of AHN: a chronic antidepressant model where DCX is upregulated and an inflammation model where DCX is downregulated. We concluded that assessing the number of DCX-expressing cells alone to quantify levels of AHN can be complex and that caution should be applied when label retention techniques are unavailable.

Automated summary

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). We found that beta-arrestin-2 (beta-Arr2) is required for the antidepressant-like effects of fluoxetine, and that its absence results in the loss of fluoxetine's effects on neural progenitor proliferation and adult-born granule cell survival. Surprisingly, fluoxetine increased the number of doublecortin (DCX)-expressing cells in beta-Arr2 knockout mice, suggesting that DCX expression can be upregulated independent of AHN. Assessing the number of DCX-expressing cells alone may not accurately quantify AHN levels.