Sensitive and Treatable Periods of Brain-Redox Imbalance in Schizophrenia

描述（由申请人提供）：一项重要的研究支持这样一种观点，即皮层快速脉冲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。来自神经发育动物模型的最新数据表明，小白蛋白（PV）阳性的快速抑制神经元的功能丧失可能发生在出生后发育的早期，特别是在它们成熟的关键时期。这些结果强烈提示，这一基本抑制系统的活跃成熟期可能是一个敏感期，在此期间，遗传和环境因素的融合可能为青春期晚期/成年早期精神分裂症样症状的发展奠定了基础。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。本项目将测试两个主要假设：(1)pv -神经元间回路的成熟期是一个敏感期，在这个敏感期，由于IL-6/Nox2通路的激活，大脑氧化应激增加，导致成年早期的精神分裂症样行为；(2)这个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”。这些假设将在小鼠身上进行测试，这些小鼠受到两种已知会导致PV-神经元间回路中断和成年早期精神分裂症相关行为的发育操作：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）。目标1将验证pNM和SI模型中存在一个大脑氧化还原失调敏感期的假设，该敏感期会导致青春期晚期/成年早期的精神分裂症样神经化学和行为中断。目的2将确定两种发育模型中脑和循环IL-6的增加是否与脑活性氧化应激相关，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是否在IL-6 KO小鼠中不存在神经化学和行为影响。最后，Aim 3将评估早期或晚期干预是否会导致脑氧化应激的衰减，通过使用Nox2抑制剂（罗花麻素），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pvv -神经元间系统并防止青春期晚期/成年早期精神分裂症样行为的发展。公共卫生影响：该项目研究一组特定的抑制神经元，这些神经元对正常认知功能至关重要，并且已知在精神分裂症中功能失调。这些研究可能建议在生命早期采用新的抗炎和/或抗氧化治疗来保护这一基本的gaba能系统，从而预防精神分裂症和其他精神疾病的发展。

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.