Favilla Christopher, Abel Ted, Kelly Michele P
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
J Neurosci. 2008 Dec 17;28(51):13952-6. doi: 10.1523/JNEUROSCI.4986-08.2008.
Current research in the field of anxiety disorders is largely receptor-centric, leaving intracellular pathways largely unexplored. Galphas, the G-protein which stimulates adenylyl cyclase and L-type voltage-gated calcium channels, may be one intracellular molecule regulating anxiety-related behaviors as increased efficacy of Galphas signaling has been noted in patient populations that suffer from anxiety. We report here anxiety-related behaviors in two lines of transgenic mice expressing a constitutively active isoform of Galphas (or Galphas*). The first line expressed Galphas* throughout postnatal forebrain neurons, while the second line of mice conditionally expressed Galphas* selectively in the striatum (Galphas*(str) mice). In the open field, both lines of mice showed a significant preference for the periphery suggesting that expression of Galphas* in the striatum alone was sufficient to produce an anxiogenic phenotype. In the light/dark box, Galphas*(str) mice exhibited longer latencies to enter the light and spent significantly less time in the lit compartment. Similarly, Galphas*(str) mice showed longer latencies to enter the open quadrants and spent less time in the open quadrants of the elevated zero maze. Interestingly, these anxiety-related phenotypes were largely unrelated to developmental effects as mice expressing the Galphas*(str) transgene during development, but not at testing, were normal on most measures. These observations show that chronic Galphas signaling in the striatum is sufficient to trigger anxiety-related behaviors largely independent of developmental effects and suggest the cAMP pathway or L-type voltage-gated calcium channels may be viable targets for future pharmacological intervention in the treatment of anxiety disorders.
目前焦虑症领域的研究主要以受体为中心，细胞内信号通路在很大程度上未被探索。Gαs是一种刺激腺苷酸环化酶和L型电压门控钙通道的G蛋白，它可能是调节焦虑相关行为的一种细胞内分子，因为在患有焦虑症的患者群体中已注意到Gαs信号传导效率的提高。我们在此报告了两系表达组成型活性Gαs（或Gαs*）亚型的转基因小鼠的焦虑相关行为。第一系在整个出生后前脑神经元中表达Gαs*，而第二系小鼠在纹状体中选择性地条件性表达Gαs*（Gαs*(str)小鼠）。在旷场实验中，两系小鼠都对周边区域表现出明显的偏好，这表明仅在纹状体中表达Gαs就足以产生致焦虑表型。在明暗箱实验中，Gαs(str)小鼠进入亮区的潜伏期更长，且在亮区停留的时间明显更短。同样，Gαs*(str)小鼠进入高架零迷宫开放象限的潜伏期更长，在开放象限停留的时间更少。有趣的是，这些焦虑相关表型在很大程度上与发育效应无关，因为在发育期间而非测试时表达Gαs*(str)转基因的小鼠在大多数指标上都是正常 的。这些观察结果表明，纹状体中的慢性Gαs信号传导足以触发焦虑相关行为，且在很大程度上独立于发育效应，并提示cAMP信号通路或L型电压门控钙通道可能是未来治疗焦虑症药物干预的可行靶点。
