Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD.

关于双相情感障碍 (BD) 的大规模全基因组关联研究 (GWAS) 表明脂肪酸去饱和酶 ( FADS ) 位点参与其中。这些酶（FADS1 和 FADS2）参与二十碳五烯酸 (EPA) 和二十二碳六烯酸 (DHA) 的代谢，被认为可能对情绪障碍患者有益。为了模拟受易感等位基因影响的 FADS1/2 活性降低，我们生成了杂合性缺乏Fads1 / 2基因的突变小鼠。我们测量了六个月的轮跑活动，并观察了活动的双相波动，包括​​多动和少动。多动症发作时的活动远高于正常水平，通常持续半天；在这些事件期间进行的行为绝望测试中，小鼠表现出明显更短的不动时间。持续数周的活动减退发作伴随着昼夜节律异常和车轮运转的显着减少，这是一种与动机和奖励系统相关的自发行为。我们全面检查了大脑中的脂质成分，发现野生型和杂合突变小鼠之间某些脂质的水平发生了显着改变，但两性没有一致的变化，并且 DHA 或 EPA 没有改变。然而，补充 DHA 或 DHA 和 EPA 混合物可以防止这些偶发的行为变化。在这里，我们提出杂合子Fads1 / 2敲除小鼠是 BD 模型，具有强大的本构效度、面部效度和预测效度，因为给予情绪稳定剂锂也有效。 这种基于 GWAS 的模型有助于阐明脂质及其代谢如何参与 BD 的发病机制和治疗。