Sarnyai Zoltán, Jashar Cassandra, Olivier Berend
Discipline of Physiology and Pharmacology, James Cook University, Townsville, QLD, Australia; Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, QLD, Australia; Comparative Genome Centre, James Cook University, Townsville, QLD, Australia; Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University, Townsville, QLD, Australia.
Discipline of Physiology and Pharmacology, James Cook University, Townsville, QLD, Australia.
Behav Brain Res. 2015 Jan 1;276:130-42. doi: 10.1016/j.bbr.2014.04.016. Epub 2014 Apr 18.
Schizophrenia is a chronic, debilitating disorder with a complex behavioral and cognitive phenotype underlined by a similarly complex etiology involving an interaction between susceptibility genes and environmental factors during early development. Limited progress has been made in developing novel pharmacotherapy, partly due to a lack of valid animal models. The recent recognition of the potentially causal role of central and peripheral energy metabolism in the pathophysiology of schizophrenia raises the need of research on animal models that combine both behavioral and metabolic phenotypic domains, similar to what have been identified in humans. In this review we focus on selected genetic (DBA/2J mice, leptin receptor mutants, and PSD-93 knockout mice), early neurodevelopmental (maternal protein deprivation) and pharmacological (acute phencyclidine) animal models that capture the combined behavioral and metabolic abnormalities shown by schizophrenic patients. In reviewing behavioral phenotypes relevant to schizophrenia we apply the principles established by the Research Domain Criteria (RDoC) for better translation. We demonstrate that etiologically diverse manipulations such as specific breeding, deletion of genes that are primarily involved in metabolic regulation and in synaptic plasticity, as well as early metabolic deprivation and adult pharmacological challenge of the glutamate system can lead to schizophrenia-related behavioral and metabolic phenotypes, which suggest that these pathways might be interlinked. We propose that using animal models that combine different domains of schizophrenia can be used as a translationally valid approach to capture the system-level complex interplay between peripheral and central processes in the development of psychopathology.
精神分裂症是一种慢性、使人衰弱的疾病，具有复杂的行为和认知表型，其病因同样复杂，涉及早期发育过程中易感基因与环境因素之间的相互作用。在开发新型药物治疗方面进展有限，部分原因是缺乏有效的动物模型。最近认识到中枢和外周能量代谢在精神分裂症病理生理学中可能具有因果作用，这就需要对结合行为和代谢表型领域的动物模型进行研究，类似于在人类中所确定的情况。在这篇综述中，我们重点关注选定的遗传（DBA/2J小鼠、瘦素受体突变体和PSD-93基因敲除小鼠）、早期神经发育（母体蛋白质剥夺）和药理学（急性苯环己哌啶）动物模型，这些模型捕捉了精神分裂症患者表现出的行为和代谢异常的综合情况。在回顾与精神分裂症相关的行为表型时，我们应用研究领域标准（RDoC）确立的原则以实现更好的转化。我们证明，病因各异的操作，如特定育种、删除主要参与代谢调节和突触可塑性的基因，以及早期代谢剥夺和对谷氨酸系统的成年药理学挑战，都可导致与精神分裂症相关的行为和代谢表型，这表明这些途径可能相互关联。我们提出，使用结合精神分裂症不同领域的动物模型可作为一种具有转化效度的方法，以捕捉精神病理学发展过程中外周和中枢过程之间系统层面的复杂相互作用。
