title: Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a.
abstract: Major depressive disorder is among the most commonly diagnosed disabling mental diseases. Several non-pharmacological treatments of depression upregulate adenosine concentration and/or adenosine A1 receptors (A1R) in the brain. To test whether enhanced A1R signaling mediates antidepressant effects, we generated a transgenic mouse with enhanced doxycycline-regulated A1R expression, specifically in forebrain neurons. Upregulating A1R led to pronounced acute and chronic resilience toward depressive-like behavior in various tests. Conversely, A1R knockout mice displayed an increased depressive-like behavior and were resistant to the antidepressant effects of sleep deprivation (SD). Various antidepressant treatments increase homer1a expression in medial prefrontal cortex (mPFC). Specific siRNA knockdown of homer1a in mPFC enhanced depressive-like behavior and prevented the antidepressant effects of A1R upregulation, SD, imipramine, and ketamine treatment. In contrast, viral overexpression of homer1a in the mPFC had antidepressant effects. Thus, increased expression of homer1a is a final common pathway mediating the antidepressant effects of different antidepressant treatments.
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, 79104 Freiburg, Germany.
authors.forename: Tsvetan
authors.initials: T
authors.lastname: Serchov
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Center Freiburg, 79104 Freiburg, Germany.
authors.forename: Hans-Willi
authors.initials: HW
authors.lastname: Clement
authors.affiliation: Functional Neuroconnectomics Group, Department of Epileptology, Life and Brain Centre, University of Bonn, Medical School, 53105 Bonn, Germany.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Schwarz
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Felice
authors.initials: F
authors.lastname: Iasevoli
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.affiliation: Department of Pneumology, University Medical Center, 79104 Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: de Bartolomeis
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, 79104 Freiburg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Normann
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, 79104 Freiburg, Germany; Department of Neuroscience, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, the Netherlands. Electronic address: knut.biber@uniklinik-freiburg.de.
authors.forename: Knut
authors.initials: K
authors.lastname: Biber
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, 79104 Freiburg, Germany. Electronic address: dietrich.calker@uniklinik-freiburg.de.
authors.forename: Dietrich
authors.initials: D
authors.lastname: van Calker
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis*; D003863:Depression / Q000378:metabolism* / Q000523:psychology / Q000628:therapy; D000072233:Homer Scaffolding Proteins; D006801:Humans; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use*; D007649:Ketamine / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000096:biosynthesis* / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012892:Sleep Deprivation / Q000378:metabolism* / Q000523:psychology
chemical_list: D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D043682:Receptor, Adenosine A1; D007649:Ketamine; D007099:Imipramine