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Genetic and clinical factors predict lithium's effects on PER2 gene expression rhythms in cells from bipolar disorder patients.

McCarthy MJ, Wei H, Marnoy Z, Darvish RM, McPhie DL, Cohen BM, Welsh DK - Transl Psychiatry (2013)

Bottom Line: Li 1 mM increased amplitude in controls by 36%, but failed to do so in BD cases.Analysis of clock gene variants revealed that PER3 and RORA genotype predicted period lengthening by Li, whereas GSK3β genotype predicted rhythm effects of Li, specifically among BD cases.Our work suggests that the circadian clock's response to Li may be relevant to molecular pathology of BD.

View Article: PubMed Central - PubMed

Affiliation: 1] Psychiatry Service, Veterans Affairs San Diego Healthcare System, University of California, San Diego, CA, USA [2] Department of Psychiatry, University of California, San Diego, CA, USA [3] Center for Chronobiology, University of California, San Diego, CA, USA.

ABSTRACT
Bipolar disorder (BD) is associated with abnormal circadian rhythms. In treatment responsive BD patients, lithium (Li) stabilizes mood and reduces suicide risk. Li also affects circadian rhythms and expression of 'clock genes' that control them. However, the extent to which BD, Li and the circadian clock share common biological mechanisms is unknown, and there have been few direct measurements of clock gene function in samples from BD patients. Hence, the role of clock genes in BD and Li treatment remains unclear. Skin fibroblasts from BD patients (N=19) or healthy controls (N=19) were transduced with Per2::luc, a rhythmically expressed, bioluminescent circadian clock reporter gene, and rhythms were measured for 5 consecutive days. Rhythm amplitude and period were compared between BD cases and controls with and without Li. Baseline period was longer in BD cases than in controls. Li 1 mM increased amplitude in controls by 36%, but failed to do so in BD cases. Li 10 mM lengthened period in both BD cases and controls. Analysis of clock gene variants revealed that PER3 and RORA genotype predicted period lengthening by Li, whereas GSK3β genotype predicted rhythm effects of Li, specifically among BD cases. Analysis of BD cases by clinical history revealed that cells from past suicide attempters were more likely to show period lengthening with Li 1 mM. Finally, Li enhanced the resynchronization of damped rhythms, suggesting a mechanism by which Li could act therapeutically in BD. Our work suggests that the circadian clock's response to Li may be relevant to molecular pathology of BD.

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Li improves rhythm resynchronization. Cellular rhythms (N=10 each BD and control) were measured without treatment until damped (dashed line, day 1–5 in panel a). In order to restore rhythms, medium change with Li 10 mM (red) or vehicle (black) was performed on day 5.5 (arrow in panel a). Omitting the signal artifact associated with media change, rhythms were then measured another 2 days (solid line in panel a). After media change, Li-treated cells had (b) significantly higher rhythm amplitudes (P<0.05), and (c) lower periods (P<0.001) compared with vehicle-treated cells. Following media change, period in Li-treated cells was in the circadian range (23.1±0.5 h (Ave±s.e.m.)); whereas period in the vehicle-treated cells was not (31.1±1.9 h (Ave±s.e.m.)).
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fig4: Li improves rhythm resynchronization. Cellular rhythms (N=10 each BD and control) were measured without treatment until damped (dashed line, day 1–5 in panel a). In order to restore rhythms, medium change with Li 10 mM (red) or vehicle (black) was performed on day 5.5 (arrow in panel a). Omitting the signal artifact associated with media change, rhythms were then measured another 2 days (solid line in panel a). After media change, Li-treated cells had (b) significantly higher rhythm amplitudes (P<0.05), and (c) lower periods (P<0.001) compared with vehicle-treated cells. Following media change, period in Li-treated cells was in the circadian range (23.1±0.5 h (Ave±s.e.m.)); whereas period in the vehicle-treated cells was not (31.1±1.9 h (Ave±s.e.m.)).

Mentions: The effect of Li on amplitude suggests that the drug may bolster weak or failing rhythms in vulnerable cell populations, by improving rhythm amplitude. We tested this hypothesis in fibroblasts from control and BD subjects. Rhythms in untreated cells were allowed to damp over 5 days, and were then subjected to medium change, a stimulus commonly used to resynchronize rhythms in cell cultures. The medium change partially restored rhythms in the absence of Li, but the resulting rhythm was typically weak with low amplitude and period exceeding the duration typically considered circadian (>30 h), consistent with poor synchronization among cells. When Li 10 mM was included in the medium, rhythms were more robustly restored, more closely resembling the initial signal, with higher amplitude and period closer to 24 h (Figures 4a–c). Statistical analysis revealed significant medium change × drug interactions for both amplitude (P<0.04, Figure 4a) and period (P<0.0001, Figure 4b), favoring rhythm restoration in Li-treated cells. The augmentation of rhythms by Li was similar in BD cases and controls (N=5 Li treated of each), suggesting that despite the relative insensitivity of BD cells to Li compared with controls when rhythms are robust, BD cells remain Li sensitive when synchronization and/or amplitudes are weak and that therapeutic benefits of Li related to clock function in BD may be preferentially engaged when rhythms are attenuated.


Genetic and clinical factors predict lithium's effects on PER2 gene expression rhythms in cells from bipolar disorder patients.

McCarthy MJ, Wei H, Marnoy Z, Darvish RM, McPhie DL, Cohen BM, Welsh DK - Transl Psychiatry (2013)

Li improves rhythm resynchronization. Cellular rhythms (N=10 each BD and control) were measured without treatment until damped (dashed line, day 1–5 in panel a). In order to restore rhythms, medium change with Li 10 mM (red) or vehicle (black) was performed on day 5.5 (arrow in panel a). Omitting the signal artifact associated with media change, rhythms were then measured another 2 days (solid line in panel a). After media change, Li-treated cells had (b) significantly higher rhythm amplitudes (P<0.05), and (c) lower periods (P<0.001) compared with vehicle-treated cells. Following media change, period in Li-treated cells was in the circadian range (23.1±0.5 h (Ave±s.e.m.)); whereas period in the vehicle-treated cells was not (31.1±1.9 h (Ave±s.e.m.)).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3818008&req=5

fig4: Li improves rhythm resynchronization. Cellular rhythms (N=10 each BD and control) were measured without treatment until damped (dashed line, day 1–5 in panel a). In order to restore rhythms, medium change with Li 10 mM (red) or vehicle (black) was performed on day 5.5 (arrow in panel a). Omitting the signal artifact associated with media change, rhythms were then measured another 2 days (solid line in panel a). After media change, Li-treated cells had (b) significantly higher rhythm amplitudes (P<0.05), and (c) lower periods (P<0.001) compared with vehicle-treated cells. Following media change, period in Li-treated cells was in the circadian range (23.1±0.5 h (Ave±s.e.m.)); whereas period in the vehicle-treated cells was not (31.1±1.9 h (Ave±s.e.m.)).
Mentions: The effect of Li on amplitude suggests that the drug may bolster weak or failing rhythms in vulnerable cell populations, by improving rhythm amplitude. We tested this hypothesis in fibroblasts from control and BD subjects. Rhythms in untreated cells were allowed to damp over 5 days, and were then subjected to medium change, a stimulus commonly used to resynchronize rhythms in cell cultures. The medium change partially restored rhythms in the absence of Li, but the resulting rhythm was typically weak with low amplitude and period exceeding the duration typically considered circadian (>30 h), consistent with poor synchronization among cells. When Li 10 mM was included in the medium, rhythms were more robustly restored, more closely resembling the initial signal, with higher amplitude and period closer to 24 h (Figures 4a–c). Statistical analysis revealed significant medium change × drug interactions for both amplitude (P<0.04, Figure 4a) and period (P<0.0001, Figure 4b), favoring rhythm restoration in Li-treated cells. The augmentation of rhythms by Li was similar in BD cases and controls (N=5 Li treated of each), suggesting that despite the relative insensitivity of BD cells to Li compared with controls when rhythms are robust, BD cells remain Li sensitive when synchronization and/or amplitudes are weak and that therapeutic benefits of Li related to clock function in BD may be preferentially engaged when rhythms are attenuated.

Bottom Line: Li 1 mM increased amplitude in controls by 36%, but failed to do so in BD cases.Analysis of clock gene variants revealed that PER3 and RORA genotype predicted period lengthening by Li, whereas GSK3β genotype predicted rhythm effects of Li, specifically among BD cases.Our work suggests that the circadian clock's response to Li may be relevant to molecular pathology of BD.

View Article: PubMed Central - PubMed

Affiliation: 1] Psychiatry Service, Veterans Affairs San Diego Healthcare System, University of California, San Diego, CA, USA [2] Department of Psychiatry, University of California, San Diego, CA, USA [3] Center for Chronobiology, University of California, San Diego, CA, USA.

ABSTRACT
Bipolar disorder (BD) is associated with abnormal circadian rhythms. In treatment responsive BD patients, lithium (Li) stabilizes mood and reduces suicide risk. Li also affects circadian rhythms and expression of 'clock genes' that control them. However, the extent to which BD, Li and the circadian clock share common biological mechanisms is unknown, and there have been few direct measurements of clock gene function in samples from BD patients. Hence, the role of clock genes in BD and Li treatment remains unclear. Skin fibroblasts from BD patients (N=19) or healthy controls (N=19) were transduced with Per2::luc, a rhythmically expressed, bioluminescent circadian clock reporter gene, and rhythms were measured for 5 consecutive days. Rhythm amplitude and period were compared between BD cases and controls with and without Li. Baseline period was longer in BD cases than in controls. Li 1 mM increased amplitude in controls by 36%, but failed to do so in BD cases. Li 10 mM lengthened period in both BD cases and controls. Analysis of clock gene variants revealed that PER3 and RORA genotype predicted period lengthening by Li, whereas GSK3β genotype predicted rhythm effects of Li, specifically among BD cases. Analysis of BD cases by clinical history revealed that cells from past suicide attempters were more likely to show period lengthening with Li 1 mM. Finally, Li enhanced the resynchronization of damped rhythms, suggesting a mechanism by which Li could act therapeutically in BD. Our work suggests that the circadian clock's response to Li may be relevant to molecular pathology of BD.

Show MeSH
Related in: MedlinePlus