Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Behav Brain Res. 2012 Apr 1;229(1):244-9. doi: 10.1016/j.bbr.2012.01.031. Epub 2012 Jan 21.
Molecular and electrophysiological studies have provided evidence for a general downregulation of the GABAergic system in the Fmr1 knockout mouse. GABA(A) receptors are the main inhibitory receptors in the brain and the GABA(A) receptor was proposed as a novel target for treatment of the fragile X syndrome, the most frequent form of intellectual disability. This study examined the functionality of the GABA(A) receptor in rotarod and elevated plus maze tests with fragile X mice treated with GABA(A) receptor agonists, the benzodiazepine diazepam and the neuroactive steroid alphaxalone. In addition, the effect of GABA(A) receptor activation on the audiogenic seizure activity was determined. We proved that the GABA(A) receptor is still sensitive to GABAergic drugs as the sedative effect of diazepam resulted in a decreased latency time on the rotarod and alphaxalone had a clear anxiolytic effect in the elevated plus maze, decreasing the frequency of entries, the total time spent and the path length in the closed arms. We also observed that treatment with ganaxolone could rescue audiogenic seizures in Fmr1 knockout mice. These findings support the hypothesis that the GABA(A) receptor is a potential therapeutic target for fragile X syndrome.
分子和电生理研究为 Fmr1 敲除小鼠 GABA 能系统的普遍下调提供了证据。GABA(A)受体是大脑中的主要抑制性受体，GABA(A)受体被提议作为治疗脆性 X 综合征（最常见的智力残疾形式）的新靶点。本研究使用 GABA(A)受体激动剂苯二氮䓬类药物地西泮和神经活性甾体化合物阿尔法羟孕酮处理脆性 X 小鼠，在旋转棒和高架十字迷宫试验中检查了 GABA(A)受体的功能。此外，还确定了 GABA(A)受体激活对听觉惊厥活动的影响。我们证明 GABA(A)受体仍然对 GABA 能药物敏感，因为地西泮的镇静作用导致旋转棒上潜伏期时间缩短，而阿尔法羟孕酮在高架十字迷宫中具有明显的抗焦虑作用，减少进入次数、在封闭臂中花费的总时间和路径长度。我们还观察到，用 ganaxolone 治疗可以挽救 Fmr1 敲除小鼠的听觉惊厥。这些发现支持 GABA(A)受体是脆性 X 综合征潜在治疗靶点的假说。
