Viana Joana, Wildman Nick, Hannon Eilis, Farbos Audrey, Neill Paul O', Moore Karen, van Aerle Ronny, Paull Greg, Santos Eduarda, Mill Jonathan
University of Exeter Medical School, University of Exeter, Exeter, UK.
Biosciences, College of Life & Environmental Sciences, University of Exeter, Exeter, UK.
NPJ Schizophr. 2020 Feb 3;6(1):3. doi: 10.1038/s41537-019-0092-x.
Clozapine is an atypical antipsychotic medication that is used to treat schizophrenia patients who are resistant to other antipsychotic drugs. The molecular mechanisms mediating the effects of clozapine are not well understood and its use is often associated with severe side-effects. In this study, we exposed groups of wild-type zebrafish to two doses of clozapine ('low' (20 µg/L) and 'high' (70 µg/L)) over a 72-h period, observing dose-dependent effects on behaviour. Using RNA sequencing (RNA-seq) we identified multiple genes differentially expressed in the zebrafish brain following exposure to clozapine. Network analysis identified co-expression modules characterised by striking changes in module connectivity in response to clozapine, and these were enriched for regulatory pathways relevant to the etiology of schizophrenia. Our study highlights the utility of zebrafish as a model for assessing the molecular consequences of antipsychotic medications and identifies genomic networks potentially involved in schizophrenia.
氯氮平是一种非典型抗精神病药物，用于治疗对其他抗精神病药物耐药的精神分裂症患者。介导氯氮平作用的分子机制尚未完全明确，且其使用常伴有严重的副作用。在本研究中，我们将野生型斑马鱼分组，在72小时内给予两剂氯氮平（“低剂量”（20µg/L）和“高剂量”（70µg/L）），观察其对行为的剂量依赖性影响。使用RNA测序（RNA-seq），我们鉴定了暴露于氯氮平后斑马鱼脑中多个差异表达的基因。网络分析确定了共表达模块，其特征是模块连接性因氯氮平而发生显著变化，并且这些模块富含与精神分裂症病因相关的调控途径。我们的研究突出了斑马鱼作为评估抗精神病药物分子后果模型的实用性，并确定了可能参与精神分裂症的基因组网络。
