Pyramidal neurons of the motor cortex are selectively degenerated in Amyotrophic Lateral Sclerosis (ALS). The mechanisms underlying neuronal death in ALS are not well established. In the absence of useful biomarkers, the early increased neuronal excitability seems to be the unique characteristic of ALS. Lipid peroxidation caused by oxidative stress has been postulated as one of the possible mechanisms involved in degeneration motor cortex pyramidal neurons. This paper examines the effect of lipid peroxidation on layer V pyramidal neurons induced by cumene hydroperoxide (CH) in brain slices from wild type rats. CH induces a synaptic depression of pyramidal neurons in a time dependent manner, already observable on GABAergic synaptic transmission after 5min application of the drug. Altogether, our whole-cell patch-clamp recording data suggest that the functional changes induced by CH upon pyramidal neurons are due to pre- and postsynaptic mechanisms. CH did not alter mEPSCs or mIPSCs, but decreased the frequency, amplitude, and decay rate of spontaneous EPSCs and IPSCs. These effects may be explained by a presynaptic mechanism causing a decrease in action potential-dependent neurotransmitter release. Additionally, CH induced a postsynaptic inward current that underlies a membrane depolarization. Depressing the input flow from the inhibitory premotor interneurons causes a transient hyperexcitability (higher resistance and lower rheobase) in pyramidal neurons of the motor cortex by presumably altering a tonic inhibitory current. These findings, which resemble relevant cortical pathophysiology of ALS, point to oxidative stress, presumably by lipid peroxidation, as an important contributor to the causes underlying this disease.

中文翻译：

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氢过氧化枯烯诱导的氧化应激在大鼠原代运动皮层神经元中引起突触抑制和短暂的过度兴奋。

运动皮层的锥体神经元在肌萎缩性侧索硬化症（ALS）中选择性退化。ALS中神经元死亡的潜在机制尚未完全确立。在缺乏有用的生物标记物的情况下，早期神经元兴奋性增加似乎是ALS的独特特征。氧化应激引起的脂质过氧化被认为是运动皮层锥体神经元变性涉及的可能机制之一。本文研究了脂质过氧化对野生型大鼠脑切片中氢过氧化枯烯（CH）诱导的V层锥体神经元的影响。CH以时间依赖的方式诱导锥体神经元的突触抑制，在应用该药物5分钟后，在GABA能突触传递中已经可以观察到。共，我们的全细胞膜片钳记录数据表明，CH对锥体神经元诱导的功能变化是由于突触前和突触后机制引起的。CH不会改变mEPSC或mIPSC，但会降低自发EPSC和IPSC的频率，幅度和衰减率。这些作用可以通过突触前机制引起，该机制引起动作电位依赖性神经递质释放的减少。此外，CH诱导突触后向内电流，这是膜去极化的基础。抑制抑制性运动前神经元的输入流会通过改变强直性抑制电流，在运动皮层的锥体神经元中引起短暂的过度兴奋（较高的抵抗力和较低的rheobase）。这些发现与ALS的相关皮质病理生理相似，表明存在氧化应激，