Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium.
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Neuropharmacology. 2017 Apr;116:71-81. doi: 10.1016/j.neuropharm.2016.12.010. Epub 2016 Dec 21.
Many clinical and molecular features of the fragile X syndrome, a common form of intellectual disability and autism, can be modeled by deletion of the Fmr1 protein (Fmrp) in mice. Previous studies showed a decreased expression of several components of the GABAergic system in Fmr1 knockout mice. Here, we used this mouse model to investigate the functional consequences of Fmrp deletion on hippocampal GABAergic inhibition in the CA1-region of the hippocampus. Whole-cell patch-clamp recordings demonstrated a significantly reduced amplitude of evoked inhibitory postsynaptic currents (eIPSCs) and a decrease in the amplitude and frequency of spontaneous IPSCs. In addition, miniature IPSCs were reduced in amplitude and frequency and decayed significantly slower than mIPSCs in controls. Quantitative real-time PCR revealed a significantly lower expression of α2, β1 and δ GABA receptor subunits in the hippocampus of the juvenile mice (P22) compared to wild-type littermates. Correspondingly, we found also at the protein level reduced amounts of α2, β1 and δ subunits in Fmr1 knockout mice. Overall, these results demonstrate that the reduction in several components of the GABAergic system is already present at young age and that this reduction results in measurable abnormalities on GABA receptor-mediated phasic inhibition. These abnormalities might contribute to the behavioral and cognitive deficits of this fragile X mouse model.
脆性 X 综合征是一种常见的智力障碍和自闭症形式，其许多临床和分子特征可以通过在小鼠中删除 Fmr1 蛋白 (Fmrp) 来模拟。先前的研究表明，Fmr1 敲除小鼠中 GABA 能系统的几个成分表达降低。在这里，我们使用这种小鼠模型来研究 Fmrp 缺失对海马 CA1 区 GABA 能抑制的功能后果。全细胞膜片钳记录显示，诱发的抑制性突触后电流 (eIPSCs) 的幅度显著降低，自发性 IPSC 的幅度和频率降低。此外，在对照中，微小 IPSC 的幅度和频率降低，衰减速度明显慢于 mIPSCs。定量实时 PCR 显示，与野生型同窝仔相比，幼年小鼠 (P22) 海马中 α2、β1 和 δ GABA 受体亚基的表达显著降低。相应地，我们还发现 Fmr1 敲除小鼠中 α2、β1 和 δ 亚基的蛋白水平也降低。总的来说，这些结果表明，GABA 能系统的几个成分的减少早在幼年时就已经存在，这种减少导致 GABA 受体介导的相性抑制出现可测量的异常。这些异常可能导致这种脆性 X 小鼠模型的行为和认知缺陷。
