γ-氨基丁酸A型（GABAA）受体是一种脆性X综合征中具有治疗潜力的脆性X智力低下蛋白（FMRP）靶点。
The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome.
作者信息
Braat Sien, D'Hulst Charlotte, Heulens Inge, De Rubeis Silvia, Mientjes Edwin, Nelson David L, Willemsen Rob, Bagni Claudia, Van Dam Debby, De Deyn Peter P, Kooy R Frank
机构信息
a Department of Medical Genetics ; University of Antwerp ; Antwerp , Belgium.
i Present address: Department of Biological Sciences ; Hunter College; City University of New York ; New York , NY USA.
出版信息
Cell Cycle. 2015;14(18):2985-95. doi: 10.4161/15384101.2014.989114.
Previous research indicates that the GABAAergic system is involved in the pathophysiology of the fragile X syndrome, a frequent form of inherited intellectual disability and associated with autism spectrum disorder. However, the molecular mechanism underlying GABAAergic deficits has remained largely unknown. Here, we demonstrate reduced mRNA expression of GABAA receptor subunits in the cortex and cerebellum of young Fmr1 knockout mice. In addition, we show that the previously reported underexpression of specific subunits of the GABAA receptor can be corrected in YAC transgenic rescue mice, containing the full-length human FMR1 gene in an Fmr1 knockout background. Moreover, we demonstrate that FMRP directly binds several GABAA receptor mRNAs. Finally, positive allosteric modulation of GABAA receptors with the neurosteroid ganaxolone can modulate specific behaviors in Fmr1 knockout mice, emphasizing the therapeutic potential of the receptor.
先前的研究表明，γ-氨基丁酸A型（GABAA）能系统参与了脆性X综合征的病理生理学过程，脆性X综合征是一种常见的遗传性智力残疾形式，与自闭症谱系障碍相关。然而，GABAA能缺陷背后的分子机制在很大程度上仍不清楚。在此，我们证明了年轻的Fmr1基因敲除小鼠的皮质和小脑中GABAA受体亚基的mRNA表达降低。此外，我们表明，在Fmr1基因敲除背景下含有全长人类FMR1基因的酵母人工染色体（YAC）转基因拯救小鼠中，先前报道的GABAA受体特定亚基的表达不足可以得到纠正。此外，我们证明FMRP直接结合几种GABAA受体mRNA。最后，用神经甾体加奈索酮对GABAA受体进行正向变构调节可以调节Fmr1基因敲除小鼠的特定行为，强调了该受体的治疗潜力。
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