Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
Transl Psychiatry. 2012 Feb 21;2(2):e81. doi: 10.1038/tp.2012.6.
The idea that there is some sort of abnormality in dopamine (DA) signalling is one of the more enduring hypotheses in schizophrenia research. Opinion leaders have published recent perspectives on the aetiology of this disorder with provocative titles such as 'Risk factors for schizophrenia--all roads lead to dopamine' or 'The dopamine hypothesis of schizophrenia--the final common pathway'. Perhaps, the other most enduring idea about schizophrenia is that it is a neurodevelopmental disorder. Those of us that model schizophrenia developmental risk-factor epidemiology in animals in an attempt to understand how this may translate to abnormal brain function have consistently shown that as adults these animals display behavioural, cognitive and pharmacological abnormalities consistent with aberrant DA signalling. The burning question remains how can in utero exposure to specific (environmental) insults induce persistent abnormalities in DA signalling in the adult? In this review, we summarize convergent evidence from two well-described developmental animal models, namely maternal immune activation and developmental vitamin D deficiency that begin to address this question. The adult offspring resulting from these two models consistently reveal locomotor abnormalities in response to DA-releasing or -blocking drugs. Additionally, as adults these animals have DA-related attentional and/or sensorimotor gating deficits. These findings are consistent with many other developmental animal models. However, the authors of this perspective have recently refocused their attention on very early aspects of DA ontogeny and describe reductions in genes that induce or specify dopaminergic phenotype in the embryonic brain and early changes in DA turnover suggesting that the origins of these behavioural abnormalities in adults may be traced to early alterations in DA ontogeny. Whether the convergent findings from these two models can be extended to other developmental animal models for this disease is at present unknown as such early brain alterations are rarely examined. Although it is premature to conclude that such mechanisms could be operating in other developmental animal models for schizophrenia, our convergent data have led us to propose that rather than all roads leading to DA, perhaps, this may be where they start.
多巴胺（DA）信号异常的观点是精神分裂症研究中更持久的假说之一。有影响力的专家最近发表了关于这种疾病病因的观点，标题颇具煽动性，如“精神分裂症的风险因素——所有道路都指向多巴胺”或“精神分裂症的多巴胺假说——最后的共同途径”。也许，关于精神分裂症的另一个最持久的观点是它是一种神经发育障碍。我们这些人试图通过在动物中模拟精神分裂症的发育风险因素流行病学来了解这如何转化为异常的大脑功能，我们一直表明，这些动物成年后表现出行为、认知和药理学异常，与异常的 DA 信号一致。目前仍有一个悬而未决的问题，即宫内暴露于特定（环境）刺激物如何在成年后导致 DA 信号持续异常？在这篇综述中，我们总结了两个描述明确的发育动物模型——母体免疫激活和发育性维生素 D 缺乏——的趋同证据，这些模型开始回答这个问题。这两个模型产生的成年后代对释放或阻断 DA 的药物反应一致地表现出运动异常。此外，作为成年人，这些动物存在与 DA 相关的注意力和/或感觉运动门控缺陷。这些发现与许多其他发育动物模型一致。然而，这篇观点的作者最近将注意力重新集中在 DA 发生的早期方面，并描述了胚胎大脑中诱导或指定多巴胺能表型的基因减少以及 DA 周转率的早期变化，这表明成年后这些行为异常的起源可能可以追溯到 DA 发生的早期改变。目前尚不清楚这些模型的趋同发现是否可以扩展到这种疾病的其他发育动物模型，因为很少检查早期大脑改变。虽然现在就得出结论认为这些机制可能在其他发育动物模型中起作用还为时过早，但我们的趋同数据使我们提出，与其说所有道路都通向 DA，也许，这就是它们开始的地方。
