Entrainment of Circadian Rhythms to Temperature Reveals Amplitude Deficits in Fibroblasts from Patients with Bipolar Disorder and Possible Links to Calcium Channels.
Entrainment of Circadian Rhythms to Temperature Reveals Amplitude Deficits in Fibroblasts from Patients with Bipolar Disorder and Possible Links to Calcium Channels.
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昼夜节律对温度的影响揭示了双相情感障碍患者成纤维细胞的振幅缺陷以及与钙通道的可能联系。
DOI：
10.1159/000497354
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
McInnis
中科院分区：
文献类型：
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作者：
Nudell,Victoria;Wei,Heather;Nievergelt,Caroline;Maihofer,AdamX;Shilling,Paul;Alda,Martin;Berrettini,WadeH;Brennand,KristenJ;Calabrese,JosephR;Coryell,WilliamH;Covault,JonathanM;Frye,MarkA;Gage,Fred;Gershon,Elliot;McInnis
双相情感障碍（BD）的特征是反复发作的情绪和昼夜节律紊乱。过去的研究已经确定钙通道基因作为BD的风险位点。CACNA 1C编码L型钙通道（LTCC），参与昼夜节律对光的诱导。另一种钙通道，即兰尼碱受体（RYR），参与昼夜节律相位延迟。目前尚不清楚CACNA 1C或其他钙通道的变异是否有助于BD的昼夜节律表型。我们假设，通过使用温度循环，我们可以模拟BD患者和对照组成纤维细胞的昼夜节律夹带，以询问LTCC的昼夜节律功能。使用Per 2-luc，一种生物发光报告基因，我们验证了细胞在体外夹带温度节律。在恒温条件下，LTCC拮抗剂维拉帕米缩短昼夜节律周期，RYR拮抗剂丹曲林延长周期。然而，这两种药物都不影响温度夹带。来自BD患者和对照的成纤维细胞也被夹带到温度。在来自BD患者的细胞中，在夹带但不恒定的条件下，节律振幅较低。BD和对照细胞之间的温度夹带在其他方面相似。然而，BD细胞中的CACNA 1C基因型预测了细胞夹带的程度。我们的结论是，在夹带条件下的节奏评估揭示了额外的节奏异常，在恒定温度条件下是不可观察的BD。
Bipolar disorder (BD) is characterized by recurrent mood episodes, and circadian rhythm disturbances. Past studies have identified calcium channel genes as risk loci for BD. CACNA1C encodes an L-type calcium channel (LTCC) involved in the entrainment of circadian rhythms to light. Another calcium channel, ie, the ryanodine receptor (RYR), is involved in-circadian phase delays. It is unknown whether variants in CACNA1C or other calcium channels contribute to the circadian phenotype in BD. We hypothesized that, by using temperature cycles, we could model circadian entrainment in fibroblasts from BD patients and controls to interrogate the circadian functions of LTCCs. Using Per2-luc, a bioluminescent reporter, we verified that cells entrain to temperature rhythms in vitro. Under constant temperature conditions, the LTCC antagonist verapamil shortened the circadian period, and the RYR antagonist dantrolene lengthened the period. However, neither drug affected temperature entrainment. Fibroblasts from BD patients and controls also entrained to temperature. In cells from BD patients, the rhythm amplitude was lower under entrained, but not constant, conditions. Temperature entrainment was otherwise similar between BD and control cells. However, the CACNA1C genotype among BD cells predicted the degree to which cells entrained. We conclude that assessment of rhythms under entrained conditions reveals additional rhythm abnormalities in BD that are not observable under constant temperature conditions.