Physiology and Behaviour Laboratory, Swiss Federal Institute of Technology (ETH) Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
Prog Neuropsychopharmacol Biol Psychiatry. 2013 Apr 5;42:20-34. doi: 10.1016/j.pnpbp.2011.11.003. Epub 2011 Nov 15.
There is increasing interest in and evidence for altered immune factors in the etiology and pathophysiology of schizophrenia. Stimulated by various epidemiological findings reporting elevated risk of schizophrenia following prenatal exposure to infection, one line of current research aims to explore the potential contribution of immune-mediated disruption of early brain development in the precipitation of long-term psychotic disease. Since the initial formulation of the "prenatal cytokine hypothesis" more than a decade ago, extensive epidemiological research and remarkable advances in modeling prenatal immune activation effects in animal models have provided strong support for this hypothesis by underscoring the critical role of cytokine-associated inflammatory events, together with downstream pathophysiological processes such as oxidative stress, hypoferremia and zinc deficiency, in mediating the short- and long-term neurodevelopmental effects of prenatal infection. Longitudinal studies in animal models further indicate that infection-induced developmental neuroinflammation may be pathologically relevant beyond the antenatal and neonatal periods, and may contribute to disease progression associated with the gradual development of full-blown schizophrenic disease. According to this scenario, exposure to prenatal immune challenge primes early pre- and postnatal alterations in peripheral and central inflammatory response systems, which in turn may disrupt the normal development and maturation of neuronal systems from juvenile to adult stages of life. Such developmental neuroinflammation may adversely affect processes that are pivotal for normal brain maturation, including myelination, synaptic pruning, and neuronal remodeling, all of which occur to a great extent during postnatal brain maturation. Undoubtedly, our understanding of the role of developmental neuroinflammation in progressive brain changes relevant to schizophrenia is still in infancy. Identification of these mechanisms would be highly warranted because they may represent a valuable target to attenuate or even prevent the emergence of full-blown brain and behavioral pathology, especially in individuals with a history of prenatal complications such as in-utero exposure to infection and/or inflammation.
人们对精神分裂症的病因和病理生理学中免疫因素的改变越来越感兴趣，并提供了越来越多的证据。受各种流行病学研究结果的启发，这些研究报告称，产前感染会增加精神分裂症的风险，目前的研究方向旨在探索免疫介导的早期大脑发育中断在引发长期精神病中的潜在作用。自从十多年前最初提出“产前细胞因子假说”以来，广泛的流行病学研究和在动物模型中模拟产前免疫激活效应的显著进展为该假说提供了强有力的支持，强调了细胞因子相关炎症事件以及下游病理生理过程（如氧化应激、低铁血症和缺锌）在介导产前感染的短期和长期神经发育效应中的关键作用。动物模型的纵向研究进一步表明，感染引起的发育性神经炎症可能在产前和新生儿期之后具有病理性相关性，并可能与与完全型精神分裂症疾病逐渐发展相关的疾病进展有关。根据这种情况，产前免疫挑战会导致外周和中枢炎症反应系统的早期产前和产后改变，进而可能破坏从幼年到成年期神经元系统的正常发育和成熟。这种发育性神经炎症可能会对正常大脑成熟的关键过程产生不利影响，包括髓鞘形成、突触修剪和神经元重塑，所有这些过程在很大程度上都发生在出生后大脑成熟过程中。毫无疑问，我们对发育性神经炎症在与精神分裂症相关的进行性脑变化中的作用的理解仍处于起步阶段。识别这些机制是非常必要的，因为它们可能代表一个有价值的靶点，可以减轻甚至预防完全型大脑和行为病理学的出现，尤其是在有产前并发症（如宫内感染和/或炎症）史的个体中。
