Center for Neuroscience Research, Children's National Medical Center, Washington, DC, USA.
Dev Neurosci. 2011;33(5):395-403. doi: 10.1159/000332884. Epub 2011 Nov 8.
Hyperactivity, hypersensitivity to auditory stimuli, and exaggerated fear are common behavioral abnormalities observed in individuals with fragile X syndrome (FXS), a neurodevelopmental disorder that is the most common genetic cause of autism. Evidence from studies of the Fmr1 knockout (KO) mouse model of FXS supports the notion that impaired GABAergic transmission in different brain regions such as the amygdala, striatum or cerebral cortex is central to FXS behavioral abnormalities. This suggests that the GABAergic system might be an intriguing target to ameliorate some of the phenotypes in FXS. Our recent work revealed that THIP (gaboxadol), a GABA(A) receptor agonist, can restore principal neuron excitability deficits in the Fmr1 KO amygdala, suggesting that THIP may also restore some of the key behavioral abnormalities in Fmr1 KO mice. Here, we reveal that THIP significantly attenuated hyperactivity in Fmr1 KO mice, and reduced prepulse inhibition in a volume-dependent manner. In contrast, THIP did not reverse the deficits in cued fear or startle response. Thus, this study shows that enhancing GABAergic transmission can correct specific behavioral phenotypes of the Fmr1 KO mouse further supporting that targeting the GABAergic system, and specifically tonic inhibition, might be important for correcting or ameliorating some key behaviors in FXS.
过度活跃、对听觉刺激过敏和过度恐惧是脆性 X 综合征（FXS）患者常见的行为异常，FXS 是一种神经发育障碍，是自闭症最常见的遗传原因。来自 FXS 的 Fmr1 敲除（KO）小鼠模型研究的证据支持这样一种观点，即不同脑区（如杏仁核、纹状体或大脑皮层）中 GABA 能传递的受损是 FXS 行为异常的核心。这表明 GABA 能系统可能是改善 FXS 一些表型的一个有趣靶点。我们最近的工作表明，THIP（gaboxadol），一种 GABA(A)受体激动剂，可恢复 Fmr1 KO 杏仁核中的主要神经元兴奋性缺陷，这表明 THIP 也可能恢复 Fmr1 KO 小鼠的一些关键行为异常。在这里，我们发现 THIP 可显著减轻 Fmr1 KO 小鼠的过度活跃，并以体积依赖性方式降低预备脉冲抑制。相比之下，THIP 并没有逆转线索恐惧或惊跳反应的缺陷。因此，这项研究表明，增强 GABA 能传递可以纠正 Fmr1 KO 小鼠的特定行为表型，进一步支持靶向 GABA 能系统，特别是紧张性抑制，可能对纠正或改善 FXS 的一些关键行为很重要。
