Sensitive and Treatable Periods of Brain-Redox Imbalance in Schizophrenia

描述(由申请人提供)：大量研究支持这样的观点，即皮层快峰抑制系统的缺陷可能是精神分裂症相关障碍的精神特征和认知缺陷的基础。最近来自神经发育动物模型的数据表明，小白蛋白(PV)阳性的快速放电抑制神经元的功能丧失可能发生在出生后发育的早期，特别是在其成熟的关键时期。这些结果有力地表明，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，遗传和环境因素的融合可能为青春期后期/成年期早期精神分裂症样症状的发展奠定基础。因此，旨在确定影响这一抑制系统成熟过程的因素的研究可能有助于揭示精神分裂症的起源。该项目将检验两个主要假设：(1)PV-神经元间回路的成熟期构成一个敏感期，在此敏感期，由于IL-6/NOX2途径的激活，大脑中的氧化应激增加，导致成年早期的精神分裂症样行为；(2)这一敏感期也构成旨在预防精神病的药物治疗策略的“干预窗口”。这些假说将在接受两种已知导致成年早期PV神经元间回路中断和精神分裂症相关行为的发育操作的小鼠身上进行验证：即围产期暴露于NMDA受体拮抗剂氯胺酮(PNM模型)和社会隔离养育(SI模型)。将制定三个具体目标：目标1将测试假设，即在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/成年期早期精神分裂症样神经化学和行为障碍。目的2确定在两种发育模型中脑和循环中IL-6的增加是否与脑内的氧化应激有关，评估循环中的IL-6是否构成预测脑功能障碍的外周生物标志物，并检验在IL-6KO小鼠中是否缺乏SI和PNM的神经化学和行为效应。最后，目标3将评估早期或晚期干预是否通过使用NOX2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来减轻大脑氧化应激，保护PV-神经元间系统，并防止青春期后期/成年期早期精神分裂症样行为的发展。公共健康影响：这个项目研究了一组特定的抑制神经元，这些神经元对正常的认知功能至关重要，并已知在精神分裂症中存在功能障碍。拟议的研究可能会建议在生命早期进行新的抗炎和/或抗氧化治疗，以保护这一基本的GABA能系统，从而防止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.