TY - JOUR
T1 - Contributions of circadian clock genes to cell survival in fibroblast models of lithium-responsive bipolar disorder
AU - Mishra, Himanshu K.
AU - Wei, Heather
AU - Rohr, Kayla E.
AU - Ko, Insu
AU - Nievergelt, Caroline M.
AU - Maihofer, Adam X.
AU - Shilling, Paul D.
AU - Alda, Martin
AU - Berrettini, Wade H.
AU - Brennand, Kristen J.
AU - Calabrese, Joseph R.
AU - Coryell, William H.
AU - Frye, Mark
AU - Gage, Fred
AU - Gershon, Elliot
AU - McInnis, Melvin G.
AU - Nurnberger, John
AU - Oedegaard, Ketil J.
AU - Zandi, Peter P.
AU - Kelsoe, John R.
AU - McCarthy, Michael J.
N1 - Publisher Copyright:
© 2023
PY - 2023/9
Y1 - 2023/9
N2 - Bipolar disorder (BD) is characterized by mood episodes, disrupted circadian rhythms and gray matter reduction in the brain. Lithium is an effective pharmacotherapy for BD, but not all patients respond to treatment. Lithium has neuroprotective properties and beneficial effects on circadian rhythms that may distinguish lithium responders (Li-R) from non-responders (Li-NR). The circadian clock regulates molecular pathways involved in apoptosis and cell survival, but how this overlap impacts BD and/or lithium responsiveness is unknown. In primary fibroblasts from Li-R/Li-NR BD patients and controls, we found patterns of co-expression among circadian clock and cell survival genes that distinguished BD vs. control, and Li-R vs. Li-NR cells. In cellular models of apoptosis using staurosporine (STS), lithium preferentially protected fibroblasts against apoptosis in BD vs. control samples, regardless of Li-R/Li-NR status. When examining the effects of lithium treatment of cells in vitro, caspase activation by lithium correlated with period alteration, but the relationship differed in control, Li-R and Li-NR samples. Knockdown of Per1 and Per3 in mouse fibroblasts altered caspase activity, cell death and circadian rhythms in an opposite manner. In BD cells, genetic variation in PER1 and PER3 predicted sensitivity to apoptosis in a manner consistent with knockdown studies. We conclude that distinct patterns of coordination between circadian clock and cell survival genes in BD may help predict lithium response.
AB - Bipolar disorder (BD) is characterized by mood episodes, disrupted circadian rhythms and gray matter reduction in the brain. Lithium is an effective pharmacotherapy for BD, but not all patients respond to treatment. Lithium has neuroprotective properties and beneficial effects on circadian rhythms that may distinguish lithium responders (Li-R) from non-responders (Li-NR). The circadian clock regulates molecular pathways involved in apoptosis and cell survival, but how this overlap impacts BD and/or lithium responsiveness is unknown. In primary fibroblasts from Li-R/Li-NR BD patients and controls, we found patterns of co-expression among circadian clock and cell survival genes that distinguished BD vs. control, and Li-R vs. Li-NR cells. In cellular models of apoptosis using staurosporine (STS), lithium preferentially protected fibroblasts against apoptosis in BD vs. control samples, regardless of Li-R/Li-NR status. When examining the effects of lithium treatment of cells in vitro, caspase activation by lithium correlated with period alteration, but the relationship differed in control, Li-R and Li-NR samples. Knockdown of Per1 and Per3 in mouse fibroblasts altered caspase activity, cell death and circadian rhythms in an opposite manner. In BD cells, genetic variation in PER1 and PER3 predicted sensitivity to apoptosis in a manner consistent with knockdown studies. We conclude that distinct patterns of coordination between circadian clock and cell survival genes in BD may help predict lithium response.
KW - Apoptosis
KW - Bipolar disorder
KW - Circadian rhythm
KW - Lithium
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U2 - 10.1016/j.euroneuro.2023.04.009
DO - 10.1016/j.euroneuro.2023.04.009
M3 - Article
C2 - 37126998
AN - SCOPUS:85153796976
SN - 0924-977X
VL - 74
SP - 1
EP - 14
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
ER -