Sensitive and Treatable Periods of Brain-Redox Imbalance in Schizophrenia

描述（由申请人提供）：大量研究支持这样一种观点，即皮质快速尖峰抑制系统的缺陷可能是精神分裂症相关疾病的精神病特征和认知缺陷的基础。最近的数据从神经发育的动物模型表明，小白蛋白（PV）阳性的快速尖峰抑制性神经元的功能丧失可能发生在出生后的发展早期，特别是在其成熟的关键时期。这些结果强烈表明，这一基本抑制系统的活跃成熟期可能构成一个敏感期，在此期间，遗传和环境因素的汇合可能为青春期后期/成年早期精神分裂症样症状的发展奠定基础。因此，旨在确定影响这种抑制系统成熟过程的因素的研究可能会揭示精神分裂症的起源。本项目将验证两个主要假设：（1）PV-神经元间回路的成熟期是一个敏感期，在此期间，由于IL-6/Nox 2通路的激活，脑中氧化应激增加，导致成年早期的精神分裂症样行为;和（2）这一敏感期也构成了旨在预防精神病的药物治疗策略的“干预窗口”。这些假设将在接受两种发育操作的小鼠中进行测试，已知这两种发育操作会导致成年早期PV-神经元间回路和精神分裂症相关行为的破坏：即围产期暴露于NMDA受体拮抗剂氯胺酮（pNM模型）和社会隔离饲养（SI模型）。将开发三个具体目标：目标1将检验以下假设：在pNM和SI模型中存在大脑氧化还原失调的敏感期，导致青春期后期/成年早期的精神分裂症样神经化学和行为中断。目的2将确定在两种发育模型中增加的脑和循环IL-6是否与脑中的活性氧化应激相关，评估循环IL-6是否构成预测脑功能障碍的外周生物标志物，并测试SI和pNM的神经化学和行为效应是否在IL-6 KO小鼠中不存在。最后，目标3将评估是否早期或晚期干预导致脑氧化应激的衰减，通过使用Nox 2抑制剂（apocynin），IL-6阻滞剂，或通过增加N-乙酰半胱氨酸的抗氧化防御，保护PV-神经元间系统，并防止青春期后期/成年早期精神分裂症样行为的发展。公共卫生影响：该项目研究了一组特定的抑制性神经元，这些神经元对正常的认知功能至关重要，并且已知在精神分裂症中功能失调。拟议的研究可能建议在生命早期进行新的抗炎和/或抗氧化治疗，以保护这种基本的GABA能系统，从而防止精神分裂症和其他精神病的发展。 公共卫生相关性：精神分裂症影响数百万美国人，当他们达到成年早期，但到目前为止，有很少的知识发生在症状出现之前的潜在疾病过程。使用两种精神分裂症的神经发育小鼠模型，该项目将确定在出生后早期发育期间，抑制回路的成熟期是否构成大脑最容易受到氧化应激过程影响的敏感期，该过程导致特定抑制回路功能障碍和成年早期出现精神分裂症样症状。这些研究将描述在两种模型中诱导氧化应激增加的机制以及它们发生的时期，并评估预防氧化应激的策略是否改善了神经化学和行为干扰。

DESCRIPTION (provided by applicant): A significant body of research supports the idea that deficits in cortical fast-spiking inhibitory systems may underlie the psychotic features and cognitive deficits associated with schizophrenia-related disorders. Recent data from neurodevelopmental animal models indicate that the loss of function of the parvalbumin-(PV) positive fast-spiking inhibitory neurons may occur early during postnatal development, specifically during the critical period of their maturation. These results strongly suggest that the period of active maturation of this fundamental inhibitory system may constitute a sensitive period during which the confluence of genetic and environmental factors may set the stage for the development of schizophrenia-like symptoms in late adolescence/early adulthood. Thus, studies directed to determine factors that affect the maturational process of this inhibitory system may shed light into the origins of schizophrenia. This project will test two primary hypotheses: (1) that the period of maturation of PV-interneuronal circuits constitutes a sensitive period in which increased oxidative stress in brain, due to the activation of the IL-6/Nox2 pathway, leads to schizophrenia-like behavior in early adulthood; and (2) that this sensitive period also constitutes a "window of intervention" for pharmacological treatment strategies aimed at prevention of psychosis. These hypotheses will be tested in mice subjected to two developmental manipulations known to lead to disruptions in the PV- interneuronal circuitry and schizophrenia-related behaviors in early adulthood: i.e. perinatal exposure to the NMDA receptor antagonist ketamine (pNM model), and social isolation rearing (SI model). Three specific aims will be developed: Aim 1 will test the hypothesis that there is a sensitive period of brain redox dysregulation in the pNM and SI models that leads to schizophrenia-like neurochemical and behavioral disruptions in late adolescence/early adulthood. Aim 2 will determine whether increased brain and circulating IL-6 correlate with active oxidative stress in brain in the two developmental models, assess whether circulating IL-6 constitutes a peripheral biomarker predictive of brain dysfunction, and test whether the neurochemical and behavioral effects of SI and pNM are absent in IL-6 KO mice. And finally, Aim 3 will assess whether early or late interventions leading to attenuation of brain oxidative stress, by use of a Nox2 inhibitor (apocynin), an IL-6 blocker, or by increasing antioxidant defenses with N-acetyl cysteine, protects the PV-interneuronal system and prevents development of schizophrenia-like behaviors in late adolescence/early adulthood. Public Health Impact: This project studies a specific set of inhibitory neurons which are critical for normal cognitive function, and known to be dysfunctional in schizophrenia. The proposed studies may suggest novel anti-inflammatory and/or anti-oxidant treatments during early life to protect this fundamental GABAergic system and thus prevent the development of schizophrenia and other psychotic conditions. PUBLIC HEALTH RELEVANCE: Schizophrenia affects millions of Americans when they reach early adulthood, but to date, there is scarce knowledge of the underlying disease processes occurring before symptoms appear. Using two neurodevelopmental mouse models of schizophrenia, this project will determine whether the period of maturation of inhibitory circuits, during early postnatal development, constitutes a sensitive period when the brain is most vulnerable to oxidative stress processes that lead to the dysfunction of specific inhibitory circuits and the appearance of schizophrenia-like symptoms in early adulthood. These studies will delineate the mechanisms inducing the increased oxidative stress in two models and the periods when they occur, and assess whether strategies that prevent oxidative stress ameliorate the neurochemical and behavioral disruptions.