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首页> 外文期刊>Biological psychiatry >Social isolation exacerbates schizophrenia-like phenotypes via oxidative stress in cortical interneurons
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Social isolation exacerbates schizophrenia-like phenotypes via oxidative stress in cortical interneurons

机译：社会隔离通过皮层神经元的氧化应激加剧了精神分裂症样表型。

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Background: Our previous studies indicated that N-methyl-D-aspartate receptor (NMDAR) deletion from a subset of corticolimbic interneurons in the mouse brain during early postnatal development is sufficient to trigger several behavioral and pathophysiological features resembling the symptoms of human schizophrenia. Interestingly, many of these behavioral phenotypes are exacerbated by social isolation stress. However, the mechanisms underlying the exacerbating effects of social isolation are unclear. Methods: With γ-aminobutyric acid-ergic interneuron-specific NMDAR hypofunction mouse model (Ppp1r2-Cre/fGluN1 knockout [KO] mice), we investigated whether oxidative stress is implicated in the social isolation-induced exacerbation of schizophrenia-like phenotypes and further explored the underlying mechanism of elevated oxidative stress in KO mice. Results: The reactive oxygen species (ROS) level in the cortex of group-housed KO mice was normal at 8 weeks although increased at 16 weeks old. Postweaning social isolation (PWSI) augmented the ROS levels in KO mice at both ages, which was accompanied by the onset of behavioral phenotype. Chronic treatment with apocynin, an ROS scavenger, abolished markers of oxidative stress and partially alleviated schizophrenia-like behavioral phenotypes in KO mice. Markers of oxidative stress after PWSI were especially prominent in cortical parvalbumin (PV)-positive interneurons. The vulnerability of PV interneurons to oxidative stress was associated with downregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial energy metabolism and antioxidation. Conclusions: These results suggest that a PWSI-mediated impairment in antioxidant defense mechanisms, presumably mediated by PGC-1α downregulation in the NMDAR-deleted PV-positive interneurons, results in oxidative stress, which, in turn, might contribute to exacerbation of schizophrenia-like behavioral phenotypes.
机译：背景：我们以前的研究表明，在出生后早期发育过程中，小鼠脑皮质皮质间神经元子集的N-甲基-D-天冬氨酸受体（NMDAR）缺失足以引发类似于人类精神分裂症症状的多种行为和病理生理特征。有趣的是，社会隔离压力加剧了许多这些行为表型。然而，社会隔离加剧的潜在机制尚不清楚。方法：使用γ-氨基丁酸能中神经元特异的NMDAR功能低下小鼠模型（Ppp1r2-Cre / fGluN1敲除[KO]小鼠），我们研究了氧化应激是否与社会隔离诱导的精神分裂症样表型加重有关，并进一步探索了KO小鼠氧化应激升高的潜在机制。结果：成群饲养的KO小鼠皮质中的活性氧（ROS）水平在8周时是正常的，尽管在16周龄时有所增加。断奶后社会隔离（PWSI）增加了两个年龄段的KO小鼠的ROS水平，并伴有行为表型的发作。用ROS清道夫Apocynin进行的长期治疗，消除了KO小鼠的氧化应激标记并部分缓解了精神分裂症样行为表型。 PWSI后的氧化应激标记在皮质小白蛋白（PV）阳性中间神经元中尤为突出。 PV中间神经元对氧化应激的脆弱性与过氧化物酶体增殖物激活的受体γ共激活因子-1α（PGC-1α）的下调有关，后者是线粒体能量代谢和抗氧化的主要调控因子。结论：这些结果表明，PWSI介导的抗氧化防御机制损伤可能是由NMDAR缺失的PV阳性中枢神经元中PGC-1α下调介导的，导致氧化应激，继而可能加剧精神分裂症-像行为表型。

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