O'Leary C, Desbonnet L, Clarke N, Petit E, Tighe O, Lai D, Harvey R, Waddington J L, O'Tuathaigh C
Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Victor Chang Cardiac Research Institute, University of New South Wales, Darlinghurst, Australia.
Neuroscience. 2014 Sep 26;277:294-305. doi: 10.1016/j.neuroscience.2014.06.028. Epub 2014 Jun 23.
Risk of schizophrenia is likely to involve gene × environment (G × E) interactions. Neuregulin 1 (NRG1) is a schizophrenia risk gene, hence any interaction with environmental adversity, such as maternal infection, may provide further insights into the basis of the disease. This study examined the individual and combined effects of prenatal immune activation with polyriboinosinic-polyribocytidilic acid (Poly I:C) and disruption of the schizophrenia risk gene NRG1 on the expression of behavioral phenotypes related to schizophrenia. NRG1 heterozygous (NRG1 HET) mutant breeding pairs were time-mated. Pregnant dams received a single injection (5mg/kg i.p.) of Poly I:C or vehicle on gestation day 9 (GD9). Offspring were then cross-fostered to vehicle-treated or Poly I:C-treated dams. Expression of schizophrenia-related behavioral endophenotypes was assessed at adolescence and in adulthood. Combining NRG1 disruption and prenatal environmental insult (Poly I:C) caused developmental stage-specific deficits in social behavior, spatial working memory and prepulse inhibition (PPI). However, combining Poly I:C and cross-fostering produced a number of behavioral deficits in the open field, social behavior and PPI. This became more complex by combining NRG1 deletion with both Poly I:C exposure and cross-fostering, which had a robust effect on PPI. These findings suggest that concepts of G × E interaction in risk of schizophrenia should be elaborated to multiple interactions that involve individual genes interacting with diverse biological and psychosocial environmental factors over early life, to differentially influence particular domains of psychopathology, sometimes over specific stages of development.
精神分裂症的风险可能涉及基因×环境（G×E）相互作用。神经调节蛋白1（NRG1）是一种精神分裂症风险基因，因此，它与诸如母体感染等环境逆境之间的任何相互作用，都可能为该疾病的发病基础提供更多见解。本研究考察了产前用聚肌苷酸-聚胞苷酸（Poly I:C）进行免疫激活以及破坏精神分裂症风险基因NRG1对与精神分裂症相关的行为表型表达的个体影响及联合效应。NRG1杂合（NRG1 HET）突变种系的雌雄配对进行定时交配。怀孕母鼠在妊娠第9天（GD9）接受一次腹腔注射（5mg/kg）的Poly I:C或溶剂。然后将后代交叉寄养到接受溶剂处理或Poly I:C处理的母鼠处。在青春期和成年期评估与精神分裂症相关的行为内表型的表达。将NRG1破坏与产前环境损伤（Poly I:C）相结合，会导致社交行为、空间工作记忆和前脉冲抑制（PPI）出现发育阶段特异性缺陷。然而，将Poly I:C与交叉寄养相结合，会在旷场试验、社交行为和PPI中产生一些行为缺陷。将NRG1缺失与Poly I:C暴露及交叉寄养相结合，情况会变得更加复杂，这对PPI有显著影响。这些发现表明，精神分裂症风险中G×E相互作用的概念应细化为多种相互作用，即单个基因在生命早期与不同的生物和心理社会环境因素相互作用，从而对精神病理学的特定领域产生不同影响，有时这种影响会发生在特定的发育阶段。
