VA San Diego Healthcare System, San Diego, CA, USA.
Department of Psychiatry and Center for Circadian Biology, University of California San Diego, La Jolla, CA, USA.
Mol Psychiatry. 2021 Jul;26(7):3383-3394. doi: 10.1038/s41380-021-01048-7. Epub 2021 Mar 5.
Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of "clock genes" and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.
双相情感障碍（BD）是一种以反复发作的躁狂/轻躁狂、抑郁和昼夜节律异常为特征的神经精神疾病。锂是治疗 BD 的有效药物，但 30-40%的患者对治疗反应不足。先前的工作表明，锂会影响“时钟基因”的表达，锂反应者（Li-R）可以通过昼夜节律的差异与非反应者（Li-NR）区分开来。然而，Li-R 和 Li-NR 的 BD 患者神经元中的昼夜节律尚未得到评估。我们使用诱导多能干细胞（iPSC）培养来自锂反应者和匹配对照的 BD 患者的神经元前体细胞（NPC）和谷氨酸能神经元。我们在 NPC 和控制组 Li-R 的神经元中发现了 Per2-luc 表达的强烈昼夜节律，但 Li-R 的 NPC 节律周期更短。Li-NR 的节律幅度低且显著减弱。在 NPC 和神经元中，BD 组的 PER2 表达均高于对照组。在神经元中，BD 中的 PER2 蛋白水平高于对照组，尤其是 Li-NR 样本。在单细胞中，BD 组的 NPC 和神经元节律与对照组相比均不同步。锂延长了 Li-R 和对照神经元的周期，但未能改变 Li-NR 的节律。相比之下，温度适应增加了所有组的幅度，并部分恢复了 Li-NR 神经元的节律。我们得出结论，BD 中存在神经元昼夜节律异常，在 Li-NR 中最为明显。BD 的节律缺陷可能通过刺激适应途径部分可逆。
