School of Medicine, University of Western Sydney, Sydney, Australia.
Neurobiol Dis. 2011 Sep;43(3):558-64. doi: 10.1016/j.nbd.2011.05.002. Epub 2011 May 13.
Duchenne muscular dystrophy (DMD) is caused by the absence of a functional transcript of the protein dystrophin. DMD is associated with a range of cognitive deficits that are thought to result from a lack of the protein dystrophin in brain structures involved in cognitive functions. The CNS involvement extends to an impairment of cognitive abilities, with many DMD boys having significant reduction in IQ. In the cerebellum, dystrophin is normally localized at the postsynaptic membrane of GABAergic synapses on Purkinje cells. Here, we investigate the effect of an absence of dystrophin on the number of GABA(A) channels located at the synapse in cerebellar Purkinje cells of the dystrophin-deficient mdx mouse. Whole-cell patch-clamp recordings of spontaneous miniature inhibitory postsynaptic currents (mIPSCs) were performed in cerebellar slices from mdx and littermate control mice. Our results showed that the number of receptors at GABAergic synapses in the cerebellar Purkinje cell was significantly reduced in mdx mice (38.38 ± 2.95) compared to littermate controls (53.03 ± 4.11). Furthermore, when gaboxadol was added to the bath, the change in holding current in mdx mice was significantly enhanced (65.01 ± 5.89pA) compared to littermate controls (37.36 ± 3.82pA). The single channel unitary conductance and the rise and decay time of mIPSCs were not significantly different in these two groups of mice, indicating that those GABA(A) channels located at the postsynaptic sites in the mdx mice function normally.
There is a reduction in the number of functional receptors localized at GABAergic synapses in the cerebellar Purkinje cells of dystrophin-deficient mdx mice and an increase in a gaboxadol induced holding current, which is evidence for an increase in extrasynaptic GABA(A) receptors in mdx mice. We hypothesize that the absence of dystrophin, from mdx Purkinje cells, reduces the number of post-synaptic GABA(A) receptors and as a result there is an increase in extrasynaptic receptors. If similar changes occur in the CNS in boys with DMD, it will impact on the function of neural networks and may contribute to some of the motor, behavioral and cognitive impairment apparent in many boys with DMD.
杜氏肌营养不良症（DMD）是由于蛋白肌营养不良蛋白的功能性转录本缺失引起的。DMD 与一系列认知缺陷相关，这些缺陷被认为是由于脑结构中缺乏肌营养不良蛋白而导致的。中枢神经系统的受累范围包括认知能力的损害，许多 DMD 男孩的智商显著降低。在小脑，肌营养不良蛋白通常位于 GABA 能突触后膜上的蒲肯野细胞上。在这里，我们研究了缺乏肌营养不良蛋白对小脑蒲肯野细胞中 GABA（A）通道数量的影响，小脑蒲肯野细胞是肌营养不良蛋白缺陷型 mdx 小鼠中的 GABA 能突触。在小脑切片中进行全细胞膜片钳记录自发微小抑制性突触后电流（mIPSCs）。我们的结果表明，小脑蒲肯野细胞 GABA 能突触的受体数量在 mdx 小鼠中明显减少（38.38 ± 2.95）与同窝对照相比（53.03 ± 4.11）。此外，当将 gaboxadol 添加到浴液中时，mdx 小鼠的保持电流变化明显增强（65.01 ± 5.89pA）与同窝对照相比（37.36 ± 3.82pA）。这两组小鼠的单通道单位电导以及 mIPSCs 的上升和下降时间没有明显差异，表明位于 mdx 小鼠突触后部位的 GABA（A）通道正常发挥功能。
在肌营养不良蛋白缺陷型 mdx 小鼠的小脑蒲肯野细胞中，位于 GABA 能突触的功能性受体数量减少，gaboxadol 诱导的保持电流增加，这表明 mdx 小鼠中 extrasynaptic GABA（A）受体增加。我们假设 mdx 蒲肯野细胞缺乏肌营养不良蛋白会减少突触后 GABA（A）受体的数量，因此 extrasynaptic 受体增加。如果在 DMD 男孩的中枢神经系统中发生类似的变化，它将影响神经网络的功能，并可能导致许多 DMD 男孩出现的运动、行为和认知障碍。
