Robertson George S, Hori Sarah E, Powell Kelly J
Department of Psychiatry, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
J Psychiatry Neurosci. 2006 May;31(3):157-67.
The discovery of candidate susceptibility genes for schizophrenia and the generation of mice lacking proteins that reproduce biochemical processes that are disrupted in this mental illness offer unprecedented opportunities for improved modelling of this complex disorder. Several lines of evidence indicate that obstetrical complications, as well as fetal or neonatal exposure to viral infection, are predisposing events for some forms of schizophrenia. These environmental events can be modelled in animals, resulting in some of the characteristic features of schizophrenia; however, animal models have yet to be developed that encompass both environmental and genetic aspects of this mental illness. A large number of candidate schizophrenia susceptibility genes have been identified that encode proteins implicated in the regulation of synaptic plasticity, neurotransmission, neuronal migration, cell adherence, signal transduction, energy metabolism and neurite outgrowth. In support of the importance of these processes in schizophrenia, mice that have reduced levels or completely lack proteins that control glutamatergic neurotransmission, neuronal migration, cell adherence, signal transduction, neurite outgrowth and synaptic plasticity display many features reminiscent of schizophrenia. In the present review, we discuss strategies for modelling schizophrenia that involve treating mice that bear these mutations in a variety of ways to better model both environmental and genetic factors responsible for this complex mental illness according to a "two-hit hypothesis." Because rodents are able to perform complex cognitive tasks using odour but not visual or auditory cues, we hypothesize that olfactory-based tests of cognitive performance should be used to search for novel therapeutics that ameliorate the cognitive deficits that are a feature of this devastating mental disorder.
精神分裂症候选易感基因的发现，以及培育出缺乏能重现该精神疾病中被破坏的生化过程的蛋白质的小鼠，为更好地模拟这种复杂疾病提供了前所未有的机会。多项证据表明，产科并发症以及胎儿或新生儿暴露于病毒感染是某些形式精神分裂症的诱发因素。这些环境因素可以在动物身上进行模拟，从而产生一些精神分裂症的特征；然而，尚未开发出涵盖这种精神疾病环境和遗传两方面因素的动物模型。已经鉴定出大量候选精神分裂症易感基因，它们编码的蛋白质与突触可塑性、神经传递、神经元迁移、细胞黏附、信号转导、能量代谢和神经突生长的调节有关。为支持这些过程在精神分裂症中的重要性，那些控制谷氨酸能神经传递、神经元迁移、细胞黏附、信号转导、神经突生长和突触可塑性的蛋白质水平降低或完全缺乏的小鼠表现出许多类似精神分裂症的特征。在本综述中，我们讨论了模拟精神分裂症的策略，即根据“双打击假说”，以多种方式处理携带这些突变的小鼠，以便更好地模拟导致这种复杂精神疾病的环境和遗传因素。由于啮齿动物能够利用气味而非视觉或听觉线索执行复杂的认知任务，我们推测应使用基于嗅觉的认知表现测试来寻找新的治疗方法，以改善这种毁灭性精神疾病所特有的认知缺陷。
