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Neurotrophic factor-α1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone

Molecular Psychiatry volume 20, pages 744–754 (2015)Cite this article

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Abstract

Major depressive disorder is often linked to stress. Although short-term stress is without effect in mice, prolonged stress leads to depressive-like behavior, indicating that an allostatic mechanism exists in this difference. Here we demonstrate that mice after short-term (1 h per day for 7 days) chronic restraint stress (CRS), do not display depressive-like behavior. Analysis of the hippocampus of these mice showed increased levels of neurotrophic factor-α1 (NF-α1; also known as carboxypeptidase E, CPE), concomitant with enhanced fibroblast growth factor 2 (FGF2) expression, and an increase in neurogenesis in the dentate gyrus. In contrast, after prolonged (6 h per day for 21 days) CRS, mice show decreased hippocampal NF-α1 and FGF2 levels and depressive-like responses. In NF-α1-knockout mice, hippocampal FGF2 levels and neurogenesis are reduced. These mice exhibit depressive-like behavior that is reversed by FGF2 administration. Indeed, studies in cultured hippocampal neurons reveal that NF-α1 treatment directly upregulates FGF2 expression through extracellular signal-regulated kinase-Sp1 signaling. Thus, during short-term CRS, hippocampal NF-α1 expression is upregulated and has a key role in preventing the onset of depressive-like behavior through enhanced FGF2-mediated neurogenesis. To evaluate the therapeutic potential of this pathway, we examined, rosiglitazone (Rosi), a PPARγ agonist, which has been shown to have antidepressant activity in rodents and humans. Rosi upregulates FGF2 expression in a NF-α1-dependent manner in hippocampal neurons. Mice fed Rosi show increased hippocampal NF-α1 levels and neurogenesis compared with controls, thereby indicating the antidepressant action of this drug. Development of drugs that activate the NF-α1/FGF2/neurogenesis pathway can offer a new approach to depression therapy.

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Acknowledgements

This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA and in part by National Institutes of Health grant HD36015 (WCW) and the American Diabetes Association Award 7-13-BS-089 (BL-C). We thank Lynne Holtzclaw, Dr Vincent Schram in the MIC at NICHD for their help in the immunocytochemistry and confocal microscopy, Dr Cheol Lee (Program on Genomics of Differentiation, NICHD) for his helpful discussions on markers for detecting neurogenesis in the hippocampus, Drs Zhihong Jiang and Lee Eiden (NIMH) for help with the sucrose preference test. We also thank the following people from the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center: Theodore Rhodes and Christopher Means for helping with the daily restraint and forced swim tests. Thanks also to Dr Chris McBain (NICHD), Dr Owen Rennert (NICHD), Dr Harold Gainer (NINDS) and Dr Hao Yang Tan (Lieber Institute for Brain Development, Johns Hopkins University) for critical reading of the manuscript.

Author Contributions

YC, RMR, SA, BL-C, WCW and YPL designed the research; YC, RMR, DKA, VS, SRKM and ET conducted the research, YC, RMR, VS, SRKM, ET, NXC, W CW and YPL analyzed the data; YC, WCW and YPL wrote the paper.

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Authors and Affiliations

  1. Section on Cellular Neurobiology, Program on Developmental Neuroscience, Bethesda, MD, USA

    Y Cheng, S R K Murthy, V Senatorov, E Thouennon, N X Cawley & Y P Loh

  2. Department of Psychiatry and Behavioral Sciences, Durham, NC, USA

    R M Rodriguiz, D K Aryal & W C Wetsel

  3. Program in Genomics Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    S Ahn

  4. Departments of Orthopaedic Surgery and Physiology and Pharmacology, Center for Diabetes and Endocrine Research, University of Toledo Health Sciences Campus, Toledo, OH, USA

    B Lecka-Czernik

  5. Departments of Neurobiology and Cell Biology, Duke University Medical Center, Durham, NC, USA

    W C Wetsel

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Cheng, Y., Rodriguiz, R., Murthy, S. et al. Neurotrophic factor-α1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone. Mol Psychiatry 20, 744–754 (2015). https://doi.org/10.1038/mp.2014.136

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