Perineuronal nets protect fast-spiking interneurons against oxidative stress
Perineuronal nets protect fast-spiking interneurons against oxidative stress
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DOI：
10.1073/pnas.1300454110
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发表时间：
2013-05-28
影响因子：
11.1
通讯作者：
Do, Kim Q.
中科院分区：
文献类型：
--
作者：
Cabungcal, Jan-Harry;Steullet, Pascal;Do, Kim Q.
精神分裂症病理生理学的一个标志是表达小清蛋白的皮质抑制性GABA神经元的功能障碍，其对于在各种感觉和认知任务期间协调神经元同步性是必不可少的。这些快速尖峰细胞的高代谢要求可能使它们容易受到氧化还原失调和氧化应激的影响。使用携带遗传性氧化还原失衡的小鼠，我们证明了细胞外神经元束膜网，这构成了一个专门的聚阴离子基质包裹大多数这些中间神经元，因为它们成熟，在保护免受氧化应激中发挥着至关重要的作用。这些网限制了遗传受损的抗氧化系统和/或由严重环境损伤产生的过量活性氧的影响。我们观察到小白蛋白细胞周围神经元网络的鲁棒性和它们显示的细胞内氧化应激程度之间的反比关系。神经元束膜网的酶降解使得成熟的小白蛋白细胞和快速节律的神经元同步性对氧化应激更敏感。与此同时，与成熟的神经元束膜网包围的小清蛋白细胞比由较少浓缩的神经元束膜网包围的未成熟的小清蛋白细胞受到更好的保护。虽然神经元周围的网起着保护屏障的作用，但它们本身也对过量的氧化应激敏感。因此，这种保护可能反映了神经元周围网降解的氧化负担与系统维持网的能力之间的平衡。异常的神经元周围网络，观察到在死后的病人的大脑，因此可能是精神分裂症的关键抑制回路的脆弱性和功能障碍的基础。
A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.