Abstract
Serotonin (5-hydroxytryptamine, 5-HT) is a crucial signal in the neurogenic niche of the hippocampus, where it is involved in antidepressant action. Here, we utilized a new transgenic rat model (TetO-shTPH2), where brain 5-HT levels can be acutely altered based on doxycycline (Dox)-inducible shRNA-expression. On/off stimulations of 5-HT concentrations might uniquely mirror the clinical course of major depression (e.g., relapse after discontinuation of antidepressants) in humans. Specifically, we measured 5-HT levels, and 5-HT metabolite 5-HIAA, in various brain areas following acute tryptophan hydroxylase 2 (Tph2) knockdown, and replenishment, and examined behavior and proliferation and survival of newly generated cells in the dentate gyrus. We found that decreased 5-HT levels in the prefrontal cortex and raphe nuclei, but not in the hippocampus of TetO-shTPH2 rats, lead to an enduring anxious phenotype. Surprisingly, the reduction in 5-HT synthesis is associated with increased numbers of BrdU-labeled cells in the dentate gyrus. At 3 weeks of Tph2 replenishment, 5-HT levels return to baseline and survival of newly generated cells is unaffected. We speculate that the acutely induced decrease in 5-HT concentrations and increased neurogenesis might represent a compensatory mechanism.
Highlights
Pharmacotherapy for major depression frequently relies on serotonin (5-HT)-targeting medications
No significant decrease in 5-HT levels in the HC of TetO-shTPH2 rats was observed for either Dox dosage (Dox20, 79.4 ± 11.1% and Dox25, 89.6 ± 7.3% of the control value; F(2,18) = 1.660, p = 0.2142; Figure 1B)
The results with Dox25 show a successful reduction in brain 5-HT levels in prefrontal cortex (PFC) and raphe nuclei (RN), which exceeds the reduction that is achieved by oral administration [13]
Summary
Pharmacotherapy for major depression frequently relies on serotonin (5-HT)-targeting medications. BDNF concentrations were enhanced in the hippocampus and prefrontal cortex of Tph2−/− mice and rats, and Tph knock-in mice [10,11,12], possibly as a compensatory way of maintaining neurogenesis in the dentate gyrus. Using these mice, we found that the effects of citalopram (a commonly prescribed SSRI) on the generation of new neurons and on BDNF protein levels are largely separable [9]
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