Department of Physiology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL 60611, USA.
Department of Biomedical Engineering, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL 60611, USA.
Neuroscience. 2017 Oct 24;362:33-46. doi: 10.1016/j.neuroscience.2017.08.041. Epub 2017 Aug 24.
Hyperexcitability is hypothesized to contribute to the degeneration of spinal motoneurons (MNs) in amyotrophic lateral sclerosis (ALS). Studies, thus far, have not linked hyperexcitability to the intrinsic properties of MNs in the adult ALS mouse model with the G93A-mutated SOD1 protein (mSOD1). In this study, we obtained two types of measurements: ventral root recordings to assess motor output and intracellular recordings to assess synaptic properties of individual MNs. All studies were carried out in an in vitro preparation of the sacral spinal cords of mSOD1 mice and their non-transgenic (NT) littermates, both in the age range of 50-90days. Ventral root recordings revealed that maximum compound action potentials (coAPs) evoked by a short-train stimulation of corresponding dorsal roots were similar between the two types of mice. Although the progressive depression of coAPs was present during the train stimulation in all recordings, the coAP depression in mSOD1 mice was to a lesser extent, which suggests an increased firing tendency in mSOD1 MNs. Intracellular recordings showed no changes in fast excitatory postsynaptic potentials (EPSPs) in mSOD1 MNs. However, recording did show that oscillating EPSPs (oEPSPs) were induced by poly-EPSPs at a higher frequency and by less-intense electrical stimulation in mSOD1 MNs. These oEPSPs were dependent upon the activities of spinal network and N-methyl-d-aspartate receptors (NMDARs), and were subjected to riluzole modulation. Taken together, these findings revealed abnormal electrophysiology in mSOD1 MNs that could underlie ALS excitotoxicity.
超兴奋性被假设为导致肌萎缩侧索硬化症（ALS）中脊髓运动神经元（MNs）退化的原因。到目前为止，研究尚未将超兴奋性与具有 G93A 突变 SOD1 蛋白（mSOD1）的成年 ALS 小鼠模型中的 MN 的内在特性联系起来。在这项研究中，我们获得了两种类型的测量结果：腹根记录以评估运动输出和细胞内记录以评估单个 MN 的突触特性。所有研究均在 mSOD1 小鼠及其非转基因（NT）同窝仔鼠的骶骨脊髓体外标本中进行，其年龄范围均为 50-90 天。腹根记录显示，通过相应的背根短串刺激诱发的最大复合动作电位（coAP）在两种类型的小鼠之间相似。尽管在所有记录中，在串刺激期间均存在 coAP 的逐渐抑制，但 mSOD1 小鼠中的 coAP 抑制程度较小，这表明 mSOD1 MN 中的放电趋势增加。细胞内记录显示 mSOD1 MN 中的快速兴奋性突触后电位（EPSP）没有变化。但是，记录显示，在 mSOD1 MN 中，通过聚-EPSP 以更高的频率和更弱的电刺激诱导振荡 EPSP（oEPSP）。这些 oEPSP 依赖于脊髓网络和 N-甲基-D-天冬氨酸受体（NMDAR）的活动，并受到利鲁唑的调节。总之，这些发现揭示了 mSOD1 MN 中异常的电生理学，这可能是 ALS 兴奋性毒性的基础。
