title: MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity.
abstract: The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA "fingerprint" of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies.
authors: The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel; Department of Stress Neurobiology and Neurogenetics, Max-Planck Institute of Psychiatry, 80804 Munich, Germany.
authors: Orna
authors: O
authors: Issler
authors: The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors: Sharon
authors: S
authors: Haramati
authors: Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA.
authors: Evan D
authors: ED
authors: Paul
authors: Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
authors: Hiroshi
authors: H
authors: Maeno
authors: The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors: Inbal
authors: I
authors: Navon
authors: The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors: Rayya
authors: R
authors: Zwang
authors: The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors: Shosh
authors: S
authors: Gil
authors: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Helen S
authors: HS
authors: Mayberg
authors: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Boadie W
authors: BW
authors: Dunlop
authors: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, 80804 Munich, Germany.
authors: Andreas
authors: A
authors: Menke
authors: Department of Neurology and Center for Genetic Medicine, Northwestern University Feinberg Medical School, Chicago, IL 60611, USA.
authors: Rajeshwar
authors: R
authors: Awatramani
authors: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, 80804 Munich, Germany.
authors: Elisabeth B
authors: EB
authors: Binder
authors: Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
authors: Evan S
authors: ES
authors: Deneris
authors: Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA.
authors: Christopher A
authors: CA
authors: Lowry
authors: The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel; Department of Stress Neurobiology and Neurogenetics, Max-Planck Institute of Psychiatry, 80804 Munich, Germany. Electronic address: alon.chen@weizmann.ac.il.
authors: Alon
authors: A
authors: Chen
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism; D055500:Resilience, Psychological; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D012919:Social Behavior; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D035683:MicroRNAs; C549289:Mirn135 microRNA, mouse; D050486:Serotonin Plasma Membrane Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin