Graciotti Laura, Minelli Andrea, Minciacchi Diego, Procopio Antonio, Fulgenzi Gianluca
Department of Molecular Pathology and Innovative Therapies, Marche Polytechnic University, Ancona, Italy.
Neuromuscul Disord. 2008 Mar;18(3):220-6. doi: 10.1016/j.nmd.2007.11.009. Epub 2008 Jan 22.
Duchenne muscular dystrophy (DMD), a genetic disease due to dystrophin gene mutation and characterised by skeletal muscle failure, is associated with non-progressive cognitive deficits. In human and mouse brain, full-length dystrophin is localised postsynaptically in neocortical, hippocampal and cerebellar neurons. Evidence obtained in the CNS of dystrophic mice (mdx) suggested alterations of the GABAergic system. However, a direct functional evaluation of GABAergic synaptic transmission in mdx mice has not been conducted in the hippocampus, which is involved in cognitive processes and is rich in full-length dystrophin. Here, we investigated evoked and miniature inhibitory postsynaptic currents (IPSCs) in CA1 pyramidal neurons of mdx mice with patch clamp recording techniques. Results showed an increased frequency of miniature spontaneous IPSCs in mdx mice compared with controls, whereas evoked IPSCs did not show significant variations. Paired-pulse facilitation (PPF) analysis showed lack of facilitation at short intervals in mdx mice compared with that in wild-type mice. Analysis of density of synapses that innervate CA1 pyramidal cell bodies did not indicate significant differences between mdx mice and controls. Therefore, we suggest that increased miniature spontaneous IPSC frequency is due to altered pre-synaptic release probability. The present findings are discussed in the light of the accrued evidence for alterations of inhibitory synaptic transmission in the brain of dystrophic mice.
杜兴氏肌营养不良症（DMD）是一种由肌营养不良蛋白基因突变引起的遗传性疾病，其特征为骨骼肌功能衰竭，并伴有非进行性认知缺陷。在人类和小鼠大脑中，全长肌营养不良蛋白定位于新皮质、海马体和小脑神经元的突触后部位。在营养不良小鼠（mdx）的中枢神经系统中获得的证据表明，γ-氨基丁酸能系统发生了改变。然而，尚未在参与认知过程且富含全长肌营养不良蛋白的海马体中对mdx小鼠的γ-氨基丁酸能突触传递进行直接的功能评估。在此，我们使用膜片钳记录技术研究了mdx小鼠CA1锥体神经元中的诱发抑制性突触后电流（IPSCs）和微小抑制性突触后电流。结果显示，与对照组相比，mdx小鼠微小自发性IPSCs的频率增加，而诱发IPSCs未显示出显著差异。配对脉冲易化（PPF）分析表明，与野生型小鼠相比，mdx小鼠在短间隔时缺乏易化现象。对支配CA1锥体细胞体的突触密度分析表明，mdx小鼠与对照组之间没有显著差异。因此，我们认为微小自发性IPSC频率增加是由于突触前释放概率改变所致。我们根据营养不良小鼠大脑中抑制性突触传递改变的累积证据对本研究结果进行了讨论。
