Decreased GABAA receptor expression in the seizure-prone fragile X mouse
Decreased GABAA receptor expression in the seizure-prone fragile X mouse
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DOI：
10.1016/j.neulet.2004.11.087
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发表时间：
2005-04-04
影响因子：
2.5
通讯作者：
Dobkin, C
中科院分区：
文献类型：
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作者：
El Idrissi, A;Ding, XH;Dobkin, C
脆性 X 智力低下综合征是由于脆性 X 基因 FMR1 的转录沉默以及由此导致的 FMR1 产物 FMRP 的丢失所致。然而，该综合征的发病机制尚不清楚。儿童癫痫发作的患病率增加是脆性 X 综合征的一个特征，在这种疾病的脆性 X 基因敲除小鼠模型中观察到癫痫易感性增加。为了研究癫痫易感性的增加，我们检测了 FVB/N 脆性 X 小鼠中 GABA(A) 受体的表达。蛋白质印迹分析显示，成年雄性脆性 X 小鼠的皮质、海马体、间脑和脑干中受体功能所需的 GABA(A) 受体 β 亚基 (GABA(A) β) 的表达降低。脑切片的免疫组织化学分析表明 GABA(A) β 免疫反应性降低。我们还发现，在 GABA(A) β 减少的同一区域，谷氨酸脱羧酶（负责 GABA 合成的酶）的表达增加。这些结果表明，Fmrp 的缺失会导致 GABA 能系统的改变，这可能是脆弱 X 小鼠癫痫发作易感性增加的原因。这些改变也可能与人类综合症中的癫痫发作和异常行为有关。 (c) 2004 Elsevier Ireland Ltd. 保留所有权利。
The fragile X mental retardation syndrome is due to the transcriptional silence of the fragile X gene, FMR1, and to the resulting loss of the FMR1 product, FMRP. The pathogenesis of the syndrome, however, is not understood. Increased prevalence of childhood seizures is a feature of the fragile X syndrome and increased seizure susceptibility is seen in the fragile X knock out mouse model for this disorder. To investigate the increased seizure susceptibility, we examined GABA(A) receptor expression in the FVB/N fragile X mouse. Western blot analysis revealed that expression of the GABA(A) receptor beta subunit (GABA(A) beta), which is required for receptor function, was reduced in the cortex, hippocampus, diencephalon and brainstem in adult male fragile X mice. Immunohistochemical analysis of brain sections indicated a reduction in GABA(A) beta immunoreactivity. We also found increased expression of glutamic acid decarboxylase, the enzyme responsible for GABA synthesis, in the same regions that showed GABA(A) beta reduction. These results indicate that the absence of Fmrp leads to GABAergic system alterations that could account for the increased seizure susceptibility of the fragile X mouse. These alterations may also be relevant to the seizures and the abnormal behaviors in the human syndrome. (c) 2004 Elsevier Ireland Ltd. All rights reserved.