Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models
Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models
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DOI：
10.1038/tp.2012.6
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发表时间：
2012-02-01
影响因子：
6.8
通讯作者：
Meyer, U.
中科院分区：
文献类型：
--
作者：
Eyles, D.;Feldon, J.;Meyer, U.
多巴胺（DA）信号传导存在某种异常的想法是精神分裂症研究中最持久的假设之一。意见领袖最近发表了关于这种疾病病因学的观点，标题具有挑衅性，如“精神分裂症的风险因素-所有道路都通向多巴胺”或“精神分裂症的多巴胺假说-最终的共同途径”。也许，关于精神分裂症的另一个最持久的想法是，它是一种神经发育障碍。我们这些在动物中模拟精神分裂症发育风险因素流行病学的人，试图了解这如何转化为异常的脑功能，一直表明这些动物成年后表现出与异常DA信号一致的行为，认知和药理学异常。迫切的问题仍然是如何在子宫内暴露于特定的（环境）侮辱诱导持续异常的DA信号在成人？在这篇综述中，我们总结了收敛的证据，从两个良好的描述发育的动物模型，即母亲的免疫激活和发育的维生素D缺乏症，开始来解决这个问题。从这两个模型产生的成年后代一致揭示运动异常DA释放或阻断药物的反应。此外，作为成年动物，这些动物具有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，这种观点的作者最近重新关注DA个体发育的早期方面，并描述了诱导或指定多巴胺能表型在胚胎脑和DA营业额的早期变化的基因的减少，这表明这些行为异常的起源在成年人中可以追溯到DA个体发育的早期改变。目前尚不清楚这两种模型的趋同发现是否可以扩展到该疾病的其他发育动物模型，因为很少检查这种早期大脑变化。虽然现在下结论说这种机制可能在其他精神分裂症的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，也许这可能是它们开始的地方，而不是所有通往DA的道路。翻译精神病学（2012）2，e81; doi：10.1038/tp.2012.6;在线发表2012年2月21日
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. Translational Psychiatry (2012) 2, e81; doi:10.1038/tp.2012.6; published online 21 February 2012