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Cited by 62Neurogenesis and neuroplasticity mechanismsTreatment of Major DepressionNeuroscience and Neuropharmacology Research

Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment

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Brooker, S M, Gobeske, K T, Chen, J, Peng, C-Y, Kessler, J A·2017·Molecular Psychiatry
DOI 10.1038/mp.2016.160PMC PMC5378681
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Abstract

Many antidepressants stimulate adult hippocampal neurogenesis, but the mechanisms by which they increase neurogenesis and modulate behavior are incompletely understood. Here we show that hippocampal bone morphogenetic protein (BMP) signaling is modulated by antidepressant treatment, and that the changes in BMP signaling mediate effects of antidepressant treatment on neural progenitor cell proliferation and behavior. Treatment with the selective serotonin reuptake inhibitor fluoxetine suppressed BMP signaling in the adult mouse hippocampus both by decreasing levels of BMP4 ligand and increasing production of the BMP inhibitor noggin. Increasing BMP signaling in the hippocampus via viral overexpression of BMP4 blocked the effects of fluoxetine on proliferation in the dentate gyrus and on depressive behavior. Conversely, inhibiting BMP signaling via viral overexpression of noggin in the hippocampus or infusion of noggin into the ventricles exerted antidepressant and anxiolytic activity along with an increase in hippocampal neurogenesis. Similarly, conditional genetic deletion of the type II BMP receptor in Ascl1-expressing cells promoted neurogenesis and reduced anxiety- and depression-like behaviors, suggesting that neural progenitor cells contribute to the effects of BMP signaling on affective behavior. These observations indicate that BMP signaling in the hippocampus regulates depressive behavior, and that decreasing BMP signaling may be required for the effects of some antidepressants. Thus BMP signaling is a new and powerful potential target for the treatment of depression.

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  • The pro-differentiation effect of fluoxetine may be limited by its ability to reduce BMP4 expression, which may result in a decreased entry into quiescence and differentiation.

    “The pro-differentiation effect of fluoxetine may be limited also by its ability to reduce BMP4 expression, which may result in a decreased entry into quiescence and differentiation (Brooker et al., 2017, see below).”

    From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as Brooker et al., 2017

    The Results section, “Fluoxetine treatment decreases BMP signaling in the adult DG” (page unavailable), reports reduced BMP4 expression after fluoxetine treatment. The Introduction says BMP signaling promotes progenitor-cell quiescence, supporting the proposed decrease in entry into quiescence. But the Results section, “Inhibition of BMP signaling in NPCs promotes neurogenesis” (page unavailable), reports enhanced maturation into neurons when BMP signaling is inhibited, not decreased differentiation. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Fluoxetine suppresses BMP signaling in the adult mouse hippocampus by decreasing levels of BMP4 and increasing levels of the BMP inhibitor noggin.

    “In fact fluoxetine suppresses BMP signaling in the adult mouse hippocampus by both decreasing the levels of BMP4 and increasing the levels of the BMP inhibitor noggin.”

    From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as Brooker et al., 2017

  • Overexpression of BMP4 blocks the effects of fluoxetine on proliferation of dentate gyrus cells, while noggin infused into lateral ventricles exerts antidepressant activity.

    “Likewise, overexpression of BMP4 blocked the effects of fluoxetine on proliferation of dentate gyrus cells, while noggin infused into lateral ventricles exerted antidepressant activity (Brooker et al., 2017).”

    From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as Brooker et al., 2017

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Authors
Brooker, S. M., Gobeske, K. T., Chen, J., Peng, C.-Y., & Kessler, J. A.
Affiliations
Northwestern University (US)
Corresponding author
Brooker, S M
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2016-10-04
Volume
22
Issue
6
Pages
910-919
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2016.160
PMC
PMC5378681
OpenAlex
W2528708709
Cited by
61
References
64
Citations by year
2026: 6 · 2025: 8 · 2024: 7 · 2023: 4 · 2022: 6 · 2021: 5 · 2020: 9 · 2019: 6 · 2018: 3 · 2017: 7
FWCI
2.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Northwestern University
  • National Institute of Mental Health (R01MH114923)
  • National Institute of General Medical Sciences (T32GM008152)
  • National Institute of Neurological Disorders and Stroke (R01NS020778, F31NS089154)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
BMP signaling, hippocampus, antidepressant treatment, fluoxetine, adult hippocampal neurogenesis, BMP4, noggin, BMP type II receptor, ASCL1, neural progenitor proliferation, dentate gyrus, depression-like behavior, anxiety-like behavior, selective serotonin reuptake inhibitors, anxiolytic effects
MeSH terms
Animals, Antidepressive Agents, Anxiety, Depression, Depressive Disorder, Fluoxetine, Gene Expression Regulation, Hippocampus, Mice, Inbred C57BL, Neurons, Stem Cells, Anti-Anxiety Agents, Signal Transduction, Selective Serotonin Reuptake Inhibitors, Dentate Gyrus, Bone Morphogenetic Proteins, Cell Proliferation, Mice, Bone Morphogenetic Protein 4, Neurogenesis, Neural Stem Cells

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