Disinhibition of the extracellular-signal-regulated kinase restores the amplification of circadian rhythms by lithium in cells from bipolar disorder patients

Abstract

ABSTRACT:Bipolar disorder (BD) is characterized by depression, mania, and circadian rhythm abnormalities. Lithium, a treatment for BD stabilizes mood and increases circadian rhythm amplitude. However, in fibroblasts grown from BD patients, lithium has weak effects on rhythm amplitude compared to healthy controls. To understand the mechanism by which lithium differentially affects rhythm amplitude in BD cells, we investigated the extracellular-signal-regulated kinase (ERK) and related signaling molecules linked to BD and circadian rhythms. In fibroblasts from BD patients, controls and mice, we assessed the contribution of the ERK pathway to lithium-induced circadian rhythm amplification. Protein analyses revealed low phospho-ERK1/2 content in fibroblasts from BD patients vs. controls. Pharmacological inhibition of ERK1/2 by PD98059 attenuated the rhythm amplification effect of lithium, while inhibition of two related kinases, c-Jun N-terminal kinase (JNK), and P38 did not. Knockdown of the transcription factors CREB and EGR-1, downstream effectors of ERK1/2, reduced baseline rhythm amplitude, but did not alter rhythm amplification by lithium. In contrast, ELK-1 knockdown amplified rhythms, an effect that was not increased further by the addition of lithium, suggesting this transcription factor may regulate the effect of lithium on amplitude. Augmentation of ERK1/2 signaling through DUSP6 knockdown sensitized NIH3T3 cells to rhythm amplification by lithium. In BD fibroblasts, DUSP6 knockdown reversed the BD rhythm phenotype, restoring the ability of lithium to increase amplitude in these cells. We conclude that the inability of lithium to regulate circadian rhythms in BD may reflect reduced ERK activity, and signaling through ELK-1.

Entrainment of Circadian Rhythms to Temperature Reveals Amplitude Deficits in Fibroblasts from Patients with Bipolar Disorder and Possible Links to Calcium Channels

“…We reported previously that the BD-associated differences in amplitude under lithium-treated conditions involved calcium [13] and ERK signaling [12], pathways involved in photic entrainment in the SCN [14, 15, 18, 19]. The relative decrease in amplitude in the BD samples under both lithium treatment and entrained conditions may imply a loss of function in one or more of these pathways in BD.…”

“…Moreover, in cells from lithium-treated BD patients, a longer circadian period, and/or phase delays predict worse treatment outcomes [11]. The attenuation of amplitude in modulation by lithium in BD cells has been linked to LTCC, reduced calcium signaling and genetic variation in CACNA1C and downstream deficits affecting the extracellular signal-regulated kinase (ERK) signal transduction pathway [12, 13]. In the course of this work, it was discovered that ­ CACNA1C is expressed rhythmically in fibroblasts and that, in BD patients harboring the CACNA1C risk allele rs4765913 (a common T/A SNP), the rhythmic expression of CACNA1C is greatly reduced [13].…”

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

“…In fibroblasts from patients with BD, increased cyclic AMP response element‐binding protein signaling, decreased α‐aminoadipic acid, and decreased phosphorylated extracellular‐signal‐regulated kinase have been reported. In fibroblasts of BD patients, mitochondrial shape was altered .…”

Solar insolation in springtime influences age of onset of bipolar I disorder

“…Some of the current treatments for bipolar disorder act directly or indirectly on circadian mechanisms, which may contribute to therapeutic effects . Lithium modulates the expression of central and peripheral clock genes , and the amplitude and timing of effects may differ between responders and non‐responders . Lithium also has phase‐delaying properties and may resynchronize overly fast circadian rhythms .…”