Aliza P Wingo1, Eric R Velasco2, Antonio Florido2, Adriana Lori3, Dennis C Choi4, Tanja Jovanovic3, Kerry J Ressler5, Raül Andero6. 1. Atlanta VA Medical Center, Decatur, Georgia; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. 2. Institut de Neurociènces, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain. 3. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. 4. Neuroscience Institute, Georgia State University, Atlanta, Georgia. 5. Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts. 6. Institut de Neurociènces, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain; Unitat de Psicobiologia (Facultat de Psicologia), Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain. Electronic address: raul.andero@uab.cat.
Abstract
BACKGROUND: Molecular mechanisms underlying psychological sequelae of exposure to stressful experiences, such as posttraumatic stress disorder (PTSD) and depression, are not well understood. METHODS: Using convergent evidence from animal and human transcriptomic and genomic studies, we aimed to identify genetic mechanisms underlying depression and anxiety after traumatic experiences. RESULTS: From a transcriptome-wide analysis in mice, we found the Ppm1f gene to be differentially expressed in the amygdala and medial prefrontal cortex (mPFC) a week after immobilization stress. Next, we found that PPM1F messenger RNA levels in human blood were downregulated in cases with symptoms of comorbid PTSD and depression and consistently in cases with anxiety symptoms in a separate human dataset. Furthermore, we showed that a genetic variant of PPM1F, rs17759843, was associated with comorbid PTSD and depression and with PPM1F expression in both human brain and blood. Given prior reported mechanistic links between PPM1F and CAMK2 (CAMKII), we examined blood messenger RNA level of CAMK2G in humans and found it to be lower in cases with comorbid PTSD and depression. We also found that PPM1F protein levels and colocalization with CAMK2G were altered in amygdala and mPFC of male mice. Additionally, we found that a systemic dose of corticosterone blocked the depressive-like phenotype elicited by stress in female mice. Lastly, corticosterone rescued the anxiety-like phenotype and messenger RNA levels of Ppm1f in amygdala and mPFC in male mice and in mPFC of female mice. CONCLUSIONS: Taken together, our data suggest a mechanistic pathway involving PPM1F and CAMK2G in stress- and trauma-related manifestation of anxiety and depression across species.
BACKGROUND: Molecular mechanisms underlying psychological sequelae of exposure to stressful experiences, such as posttraumatic stress disorder (PTSD) and depression, are not well understood. METHODS: Using convergent evidence from animal and human transcriptomic and genomic studies, we aimed to identify genetic mechanisms underlying depression and anxiety after traumatic experiences. RESULTS: From a transcriptome-wide analysis in mice, we found the Ppm1f gene to be differentially expressed in the amygdala and medial prefrontal cortex (mPFC) a week after immobilization stress. Next, we found that PPM1F messenger RNA levels in human blood were downregulated in cases with symptoms of comorbid PTSD and depression and consistently in cases with anxiety symptoms in a separate human dataset. Furthermore, we showed that a genetic variant of PPM1F, rs17759843, was associated with comorbid PTSD and depression and with PPM1F expression in both human brain and blood. Given prior reported mechanistic links between PPM1F and CAMK2 (CAMKII), we examined blood messenger RNA level of CAMK2G in humans and found it to be lower in cases with comorbid PTSD and depression. We also found that PPM1F protein levels and colocalization with CAMK2G were altered in amygdala and mPFC of male mice. Additionally, we found that a systemic dose of corticosterone blocked the depressive-like phenotype elicited by stress in female mice. Lastly, corticosterone rescued the anxiety-like phenotype and messenger RNA levels of Ppm1f in amygdala and mPFC in male mice and in mPFC of female mice. CONCLUSIONS: Taken together, our data suggest a mechanistic pathway involving PPM1F and CAMK2G in stress- and trauma-related manifestation of anxiety and depression across species.
Authors: Kun Li; Tao Zhou; Lujian Liao; Zhongfei Yang; Catherine Wong; Fritz Henn; Roberto Malinow; John R Yates; Hailan Hu Journal: Science Date: 2013-08-30 Impact factor: 47.728
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: Alicia Mattiazzi; Rosana A Bassani; Ariel L Escobar; Julieta Palomeque; Carlos A Valverde; Martín Vila Petroff; Donald M Bers Journal: Am J Physiol Heart Circ Physiol Date: 2015-03-06 Impact factor: 4.733
Authors: Bruce S McEwen; Nicole P Bowles; Jason D Gray; Matthew N Hill; Richard G Hunter; Ilia N Karatsoreos; Carla Nasca Journal: Nat Neurosci Date: 2015-09-25 Impact factor: 24.884
Authors: Harm-Jan Westra; Marjolein J Peters; Tõnu Esko; Hanieh Yaghootkar; Claudia Schurmann; Johannes Kettunen; Mark W Christiansen; Bruce M Psaty; Samuli Ripatti; Alexander Teumer; Timothy M Frayling; Andres Metspalu; Joyce B J van Meurs; Lude Franke; Benjamin P Fairfax; Katharina Schramm; Joseph E Powell; Alexandra Zhernakova; Daria V Zhernakova; Jan H Veldink; Leonard H Van den Berg; Juha Karjalainen; Sebo Withoff; André G Uitterlinden; Albert Hofman; Fernando Rivadeneira; Peter A C 't Hoen; Eva Reinmaa; Krista Fischer; Mari Nelis; Lili Milani; David Melzer; Luigi Ferrucci; Andrew B Singleton; Dena G Hernandez; Michael A Nalls; Georg Homuth; Matthias Nauck; Dörte Radke; Uwe Völker; Markus Perola; Veikko Salomaa; Jennifer Brody; Astrid Suchy-Dicey; Sina A Gharib; Daniel A Enquobahrie; Thomas Lumley; Grant W Montgomery; Seiko Makino; Holger Prokisch; Christian Herder; Michael Roden; Harald Grallert; Thomas Meitinger; Konstantin Strauch; Yang Li; Ritsert C Jansen; Peter M Visscher; Julian C Knight Journal: Nat Genet Date: 2013-09-08 Impact factor: 38.330
Authors: William Whang; Laura D Kubzansky; Ichiro Kawachi; Kathryn M Rexrode; Candyce H Kroenke; Robert J Glynn; Hasan Garan; Christine M Albert Journal: J Am Coll Cardiol Date: 2009-03-17 Impact factor: 27.203
Authors: Sija J van der Wal; Adam X Maihofer; Christiaan H Vinkers; Alicia K Smith; Caroline M Nievergelt; Dawayland O Cobb; Monica Uddin; Dewleen G Baker; Nicolaas P A Zuithoff; Bart P F Rutten; Eric Vermetten; Elbert Geuze; Marco P Boks Journal: Compr Psychoneuroendocrinol Date: 2020-11-13
Authors: E R Velasco; A Florido; Á Flores; E Senabre; A Gomez-Gomez; A Torres; A Roca; S Norrholm; E L Newman; P Das; R A Ross; A Lori; O J Pozo; K J Ressler; L L Garcia-Esteve; T Jovanovic; R Andero Journal: Nat Commun Date: 2022-07-28 Impact factor: 17.694
Authors: Lucia Carboni; Luca Marchetti; Mario Lauria; Peter Gass; Barbara Vollmayr; Amanda Redfern; Lesley Jones; Maria Razzoli; Karim Malki; Veronica Begni; Marco A Riva; Enrico Domenici; Laura Caberlotto; Aleksander A Mathé Journal: Neuropsychopharmacology Date: 2018-06-12 Impact factor: 7.853
Authors: Danielle R Sullivan; Filomene G Morrison; Erika J Wolf; Mark W Logue; Catherine B Fortier; David H Salat; Jennifer R Fonda; Annjanette Stone; Steven Schichman; William Milberg; Regina McGlinchey; Mark W Miller Journal: J Affect Disord Date: 2019-08-19 Impact factor: 6.533