GABAB(1) receptor subunit isoforms differentially regulate stress resilience

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. GABA(B) receptors are emerging therapeutic targets for the treatment of stress-related disorders such as depression. These receptors are predominantly expressed as heterodimers of a GABA(B(2)) subunit with either a GABA(B(1a)) or a GABA(B(1b)) subunit. Here we show that mice lacking the GABA(B(1b)) receptor isoform are more resilient to both early-life stress and chronic psychosocial stress in adulthood, whereas mice lacking GABA(B(1a)) receptors are more susceptible to stress-induced anhedonia and social avoidance compared with wildtype mice. In addition, increased hippocampal expression of the GABA(B(1b)) receptor subunit is associated with a depression-like phenotype in the helpless H/Rouen genetic mouse model of depression. Stress resilience in GABA(B(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 GABA(B(1)) receptor subunit isoforms differentially regulate the deleterious effects of stress and, thus, may be important therapeutic targets for the treatment of depression.