title: GABAB(1) receptor subunit isoforms differentially regulate stress resilience.
abstract: Stressful life events increase the susceptibility to developing psychiatric disorders such as depression; however, many individuals are resilient to such negative effects of stress. Determining the neurobiology underlying this resilience is instrumental to the development of novel and more effective treatments for stress-related psychiatric disorders. GABAB receptors are emerging therapeutic targets for the treatment of stress-related disorders such as depression. These receptors are predominantly expressed as heterodimers of a GABAB(2) subunit with either a GABAB(1a) or a GABAB(1b) subunit. Here we show that mice lacking the GABAB(1b) receptor isoform are more resilient to both early-life stress and chronic psychosocial stress in adulthood, whereas mice lacking GABAB(1a) receptors are more susceptible to stress-induced anhedonia and social avoidance compared with wild-type mice. In addition, increased hippocampal expression of the GABAB(1b) receptor subunit is associated with a depression-like phenotype in the helpless H/Rouen genetic mouse model of depression. Stress resilience in GABAB(1b)(-/-) mice is coupled with increased proliferation and survival of newly born cells in the adult ventral hippocampus and increased stress-induced c-Fos activation in the hippocampus following early-life stress. Taken together, the data suggest that GABAB(1) receptor subunit isoforms differentially regulate the deleterious effects of stress and, thus, may be important therapeutic targets for the treatment of depression.
authors.affiliation: Departments of Anatomy and Neuroscience and Alimentary Pharmabiotic Centre, and o.oleary@ucc.ie j.cryan@ucc.ie.
authors.forename: Olivia F
authors.initials: OF
authors.lastname: O'Leary
authors.affiliation: School of Pharmacy, University College Cork, Cork, Ireland;
authors.forename: Daniela
authors.initials: D
authors.lastname: Felice
authors.affiliation: Departments of Anatomy and Neuroscience and.
authors.forename: Stefano
authors.initials: S
authors.lastname: Galimberti
authors.affiliation: Alimentary Pharmabiotic Centre, and.
authors.forename: Hélène M
authors.initials: HM
authors.lastname: Savignac
authors.affiliation: Alimentary Pharmabiotic Centre, and.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Bravo
authors.affiliation: Departments of Anatomy and Neuroscience and.
authors.forename: Tadhg
authors.initials: T
authors.lastname: Crowley
authors.affiliation: University of Lyon 1, 69373 Lyon Cedex 8, France; Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR 5292, 69373 Lyon Cedex 8, France;
authors.forename: Malika
authors.initials: M
authors.lastname: El Yacoubi
authors.affiliation: Department of Pharmacy, University of Rouen, 76183 Rouen Cedex 1, France; Toxicologie de l'Environnement: Milieux Aériens et Cancers/Equipe d'Accueil 4651 "Aliments Bioprocédés Toxicologie Environnements," 76183 Rouen Cedex 1, France; and.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Vaugeois
authors.affiliation: Department of Biomedicine, University of Basel, 4056 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Gassmann
authors.affiliation: Department of Biomedicine, University of Basel, 4056 Basel, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.affiliation: Alimentary Pharmabiotic Centre, and Psychiatry.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
authors.affiliation: Departments of Anatomy and Neuroscience and Alimentary Pharmabiotic Centre, and o.oleary@ucc.ie j.cryan@ucc.ie.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D059445:Anhedonia; D000818:Animals; D001522:Behavior, Animal; D049109:Cell Proliferation; D003345:Corticosterone / Q000378:metabolism; D003863:Depression / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018080:Receptors, GABA-B / Q000502:physiology*; D012307:Risk Factors; D013315:Stress, Psychological; D013550:Swimming
chemical_list: D020033:Protein Isoforms; D016760:Proto-Oncogene Proteins c-fos; D018080:Receptors, GABA-B; D003345:Corticosterone
keywords: antidepressant; anxiety; depression; neurogenesis