O'Leary Olivia F, Felice Daniela, Galimberti Stefano, Savignac Hélène M, Bravo Javier A, Crowley Tadhg, El Yacoubi Malika, Vaugeois Jean-Marie, Gassmann Martin, Bettler Bernhard, Dinan Timothy G, Cryan John F
Departments of Anatomy and Neuroscience and Alimentary Pharmabiotic Centre, and
School of Pharmacy, University College Cork, Cork, Ireland;
Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15232-7. doi: 10.1073/pnas.1404090111. Epub 2014 Oct 6.
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.
压力性生活事件会增加患抑郁症等精神疾病的易感性；然而，许多人对压力的这种负面影响具有复原力。确定这种复原力背后的神经生物学机制有助于开发针对与压力相关的精神疾病的新型且更有效的治疗方法。GABAB受体正在成为治疗抑郁症等与压力相关疾病的新兴治疗靶点。这些受体主要以GABAB(2)亚基与GABAB(1a)或GABAB(1b)亚基的异二聚体形式表达。在此我们表明，缺乏GABAB(1b)受体亚型的小鼠对成年期的早期生活压力和慢性社会心理压力更具复原力，而与野生型小鼠相比，缺乏GABAB(1a)受体的小鼠更容易出现应激诱导的快感缺失和社交回避。此外，在无助的H/Rouen遗传性抑郁症小鼠模型中，GABAB(1b)受体亚基在海马体中的表达增加与类似抑郁的表型相关。GABAB(1b)(-/-)小鼠的应激复原力与成年腹侧海马体中新生细胞的增殖和存活增加以及早期生活压力后海马体中应激诱导的c-Fos激活增加有关。综上所述，数据表明GABAB(1)受体亚基亚型对压力的有害影响有不同的调节作用，因此可能是治疗抑郁症的重要治疗靶点。
