title: Neurotrophic-priming of glucocorticoid receptor signaling is essential for neuronal plasticity to stress and antidepressant treatment.
abstract: Neurotrophins and glucocorticoids are robust synaptic modifiers, and deregulation of their activities is a risk factor for developing stress-related disorders. Low levels of brain-derived neurotrophic factor (BDNF) increase the desensitization of glucocorticoid receptors (GR) and vulnerability to stress, whereas higher levels of BDNF facilitate GR-mediated signaling and the response to antidepressants. However, the molecular mechanism underlying neurotrophic-priming of GR function is poorly understood. Here we provide evidence that activation of a TrkB-MAPK pathway, when paired with the deactivation of a GR-protein phosphatase 5 pathway, resulted in sustained GR phosphorylation at BDNF-sensitive sites that is essential for the transcription of neuronal plasticity genes. Genetic strategies that disrupted GR phosphorylation or TrkB signaling in vivo impaired the neuroplasticity to chronic stress and the effects of the antidepressant fluoxetine. Our findings reveal that the coordinated actions of BDNF and glucocorticoids promote neuronal plasticity and that disruption in either pathway could set the stage for the development of stress-induced psychiatric diseases.
authors.affiliation: Deptartment of Physiology, Institut de Genomique Fonctionnelle, INSERM U1191, CNRS UMR5203, University of Montpellier, Montpellier 34070, France; Margarita.arango@igf.cnrs.fr freddy.jeanneteau@igf.cnrs.fr.
authors.forename: Margarita
authors.initials: M
authors.lastname: Arango-Lievano
authors.affiliation: Department of Microbiology, New York University Langone Medical Center, New York, NY 10016;
authors.forename: W Marcus
authors.initials: WM
authors.lastname: Lambert
authors.affiliation: Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI 02912;
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Bath
authors.affiliation: Department of Microbiology, New York University Langone Medical Center, New York, NY 10016;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
authors.affiliation: Department of Cell Biology, Physiology, and Neuroscience and Department of Psychiatry, New York University Langone Medical Center, New York, NY 10016.
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.affiliation: Deptartment of Physiology, Institut de Genomique Fonctionnelle, INSERM U1191, CNRS UMR5203, University of Montpellier, Montpellier 34070, France; Margarita.arango@igf.cnrs.fr freddy.jeanneteau@igf.cnrs.fr.
authors.forename: Freddy
authors.initials: F
authors.lastname: Jeanneteau
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D011965:Receptors, Glucocorticoid; D005473:Fluoxetine; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human
keywords: BDNF; antidepressant; coincidence detection; glucocorticoid; stress