Braat Sien, Kooy R Frank
Department of Medical Genetics, University of Antwerp, Prins Boudewijnlaan 43, 2650 Edegem, Antwerp, Belgium.
Neuropharmacology. 2015 Jan;88:48-54. doi: 10.1016/j.neuropharm.2014.06.028. Epub 2014 Jul 10.
An increasing number of studies implicate the GABAAergic system in the pathophysiology of the fragile X syndrome, a frequent cause of intellectual disability and autism. Animal models have proven invaluable in unravelling the molecular mechanisms underlying the disorder. Multiple defects in this inhibitory system have been identified in Fmr1 knockout mice, including altered expression of various components, aberrant GABAA receptor-mediated signalling, altered GABA concentrations and anatomical defects in GABAergic neurons. Aberrations compatible with those described in the mouse model were detected in dfmr1 deficient Drosophila melanogaster, a validated fly model for the fragile X syndrome. Treatment with drugs that ameliorate the GABAAergic deficiency in both animal models have demonstrated that the GABAA receptor is a promising target for the treatment of fragile X patients. Based on these preclinical studies, clinical trials in patients have been initiated.
越来越多的研究表明，GABAA能系统参与了脆性X综合征的病理生理学过程，脆性X综合征是导致智力残疾和自闭症的常见原因。动物模型已被证明在揭示该疾病潜在的分子机制方面具有不可估量的价值。在Fmr1基因敲除小鼠中已发现该抑制系统存在多种缺陷，包括各种组分的表达改变、GABAA受体介导的信号异常、GABA浓度改变以及GABA能神经元的解剖学缺陷。在dfmr1缺陷的黑腹果蝇（一种经过验证的脆性X综合征果蝇模型）中检测到了与小鼠模型中描述的异常情况相符的畸变。在两种动物模型中使用改善GABAA能缺陷的药物进行治疗表明，GABAA受体是治疗脆性X患者的一个有前景的靶点。基于这些临床前研究，已启动了针对患者的临床试验。
