title: Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment.
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.
authors.affiliation: Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Brooker
authors.affiliation: Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Gobeske
authors.affiliation: Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Peng
authors.affiliation: Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Kessler
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism / Q000502:physiology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy; D003866:Depressive Disorder / Q000188:drug therapy; D005473:Fluoxetine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors