GABAB(1) receptor subunit isoforms differentially regulate stress resilience

Olivia F. O'Leary, Daniela Felice, Stefano Galimberti, Hélène M. Savignac, Javier A. Bravo, Tadhg Crowley, Malika El Yacoubi, Jean Marie Vaugeois, Martin Gassmann, Bernhard Bettler, Timothy G. Dinan, John F. Cryan

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

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 wildtype 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.

Original languageEnglish
Pages (from-to)15232-15237
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number42
DOIs
StatePublished - 21 Oct 2014
Externally publishedYes

Keywords

  • Antidepressant
  • Anxiety
  • Depression
  • Neurogenesis

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