Enduring Effects of Conditional Brain Serotonin Knockdown, Followed by Recovery, on Adult Rat Neurogenesis and Behavior

Cells

Rainer Hellweg¹  Golo Kronenberg²  Michael Bader³  Susann Matthes³  Markus Petermann³  Natalia Alenina³  Oksana Tuchina⁴  Friederike Klempin⁴  Maria Sidorova⁴ 

[1] Department of Psychiatry and Psychotherapy, Charité University Medicine, 10117 Berlin, Germany;Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatrische Universitätsklinik, 8032 Zürich, Switzerland;Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany;School of Life Sciences, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russia;

关键词: serotonin;    Tph2;    depression;    neurogenesis;    stem cells;    BrdU;   

DOI  :  10.3390/cells10113240

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown