Increase in Seizure Susceptibility After Repetitive Concussion Results from Oxidative Stress, Parvalbumin-Positive Interneuron Dysfunction and Biphasic Increases in Glutamate/GABA Ratio
Increase in Seizure Susceptibility After Repetitive Concussion Results from Oxidative Stress, Parvalbumin-Positive Interneuron Dysfunction and Biphasic Increases in Glutamate/GABA Ratio
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DOI：
10.1093/cercor/bhaa157
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发表时间：
2020-12-01
期刊：
影响因子：
3.7
通讯作者：
Rotenberg, Alexander
中科院分区：
文献类型：
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作者：
MacMullin, Paul;Hodgson, Nathaniel;Rotenberg, Alexander
轻度创伤性脑损伤，特别是重复性轻度创伤性脑损伤（rmTBI）后出现慢性症状，表明皮质过度兴奋。然而，创伤后兴奋/抑制（E/I）比率异常的机制可能在创伤后早期和晚期阶段之间存在差异。因此，我们测量癫痫发作阈值和皮质γ-氨基丁酸（GABA）和谷氨酸（Glu）的浓度，1和6周后rmTBI小鼠。我们还分析了小清蛋白阳性中间神经元（PVIs）的结构，它们的神经元周围网络（PNN 5）和它们的脑电图（EEG）特征（伽马频带功率）。对于机制的见解，我们测量皮质氧化应激，反映在还原/氧化谷胱甘肽（GSH/GSSG）的比例。我们发现，癫痫发作的易感性增加后早期和晚期rmTBI。然而，尽管rmTBI后1周Glu增加主导了E/I，但Glu浓度正常化，而E/I的特征在于rmTBI后6周时间点时GABA降低、PVI小白蛋白表达降低和γ EEG功率降低。氧化应激rmTBI后早期增加，其中注意到短暂的PNN降解，并在整个监测期间进展。我们的结论是，谷胱甘肽耗竭，可能引发早期谷氨酸介导的兴奋性毒性，导致后期后rmTBI损失PVI依赖的皮质抑制音。因此，我们建议抑制Glu信号传导，维持氧化还原状态，并保留PVI抑制能力作为rmTBI后治疗的治疗靶点。
Chronic symptoms indicating excess cortical excitability follow mild traumatic brain injury, particularly repetitive mild traumatic brain injury (rmTBI). Yet mechanisms underlying post-traumatic excitation/inhibition (E/I) ratio abnormalities may differ between the early and late post-traumatic phases. We therefore measured seizure threshold and cortical gamma-aminobutyric acid (GABA) and glutamate (Glu) concentrations, 1 and 6 weeks after rmTBI in mice. We also analyzed the structure of parvalbumin-positive interneurons (PVIs), their perineuronal nets (PNN5), and their electroencephalography (EEG) signature (gamma frequency band power). For mechanistic insight, we measured cortical oxidative stress, reflected in the reduced/oxidized glutathione (GSH/GSSG) ratio. We found that seizure susceptibility increased both early and late after rmTBI. However, whereas increased Glu dominated the E/I 1 week after rmTBI, Glu concentration normalized and the E/I was instead characterized by depressed GABA, reduced per-PVI parvalbumin expression, and reduced gamma EEG power at the 6-week post-rmTBI time point. Oxidative stress was increased early after rmTBI, where transient PNN degradation was noted, and progressed throughout the monitoring period. We conclude that GSH depletion, perhaps triggered by early Glu-mediated excitotoxicity, leads to late post-rmTBI loss of PVI-dependent cortical inhibitory tone. We thus propose dampening of Glu signaling, maintenance of redox state, and preservation of PVI inhibitory capacity as therapeutic targets for post-rmTBI treatment.