Luckhart Christine, Philippe Tristan J, Le François Brice, Vahid-Ansari Faranak, Geddes Sean D, Béïque Jean-Claude, Lagace Diane C, Daigle Mireille, Albert Paul R
Ottawa Hospital Research Institute (Neuroscience), Ottawa, Canada.
Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H-8M5, Canada.
Mol Brain. 2016 Aug 3;9(1):77. doi: 10.1186/s13041-016-0254-y.
The C (-1019) G rs6295 promoter polymorphism of the serotonin-1A (5-HT1A) receptor gene is associated with major depression in several but not all studies, suggesting that compensatory mechanisms mediate resilience. The rs6295 risk allele prevents binding of the repressor Deaf1 increasing 5-HT1A receptor gene transcription, and the Deaf1-/- mouse model shows an increase in 5-HT1A autoreceptor expression. In this study, Deaf1-/- mice bred on a mixed C57BL6-BALB/c background were compared to wild-type littermates for 5-HT1A autoreceptor function and behavior in males and females. Despite a sustained increase in 5-HT1A autoreceptor binding levels, the amplitude of the 5-HT1A autoreceptor-mediated current in 5-HT neurons was unaltered in Deaf1-/- mice, suggesting compensatory changes in receptor function. Consistent with increased 5-HT1A autoreceptor function in vivo, hypothermia induced by the 5-HT1A agonist DPAT was augmented in early generation male but not female Deaf1-/- mice, but was reduced with succeeding generations. Loss of Deaf1 resulted in a mild anxiety phenotype that was sex-and test-dependent, with no change in depression-like behavior. Male Deaf1 knockout mice displayed anxiety-like behavior in the open field and light-dark tests, while female Deaf1-/- mice showed increased anxiety only in the elevated plus maze. These data show that altered 5-HT1A autoreceptor regulation in male Deaf1-/- mice can be compensated for by generational adaptation of receptor response that may help to normalize behavior. The sex dependence of Deaf1 function in mice is consistent with a greater role for 5-HT1A autoreceptors in sensitivity to depression in men.
血清素1A（5-HT1A）受体基因的C（-1019）G rs6295启动子多态性在一些但并非所有研究中都与重度抑郁症相关，这表明补偿机制介导了恢复力。rs6295风险等位基因可阻止阻遏物Deaf1的结合，从而增加5-HT1A受体基因的转录，并且Deaf1基因敲除小鼠模型显示5-HT1A自身受体表达增加。在本研究中，将在C57BL6-BALB/c混合背景下培育的Deaf1基因敲除小鼠与野生型同窝小鼠在雄性和雌性小鼠中进行5-HT1A自身受体功能和行为的比较。尽管5-HT1A自身受体结合水平持续升高，但在Deaf1基因敲除小鼠中，5-HT神经元中5-HT1A自身受体介导的电流幅度未发生改变，这表明受体功能发生了补偿性变化。与体内5-HT1A自身受体功能增强一致，5-HT1A激动剂DPAT诱导的体温过低在初代雄性而非雌性Deaf1基因敲除小鼠中增强，但在后续世代中减弱。Deaf1的缺失导致了一种轻度焦虑表型，该表型具有性别和试验依赖性，抑郁样行为无变化。雄性Deaf1基因敲除小鼠在旷场试验和明暗试验中表现出焦虑样行为，而雌性Deaf1基因敲除小鼠仅在高架十字迷宫试验中表现出焦虑增加。这些数据表明，雄性Deaf1基因敲除小鼠中5-HT1A自身受体调节的改变可通过受体反应的世代适应性得到补偿，这可能有助于使行为正常化。小鼠中Deaf1功能的性别依赖性与5-HT1A自身受体在男性对抑郁症敏感性中发挥更大作用相一致。
