Lithium- and Valproate-Induced Alterations in Circadian Locomotor Behavior in Drosophila

Abstract

Lithium and valproate are commonly used mood stabilizers, but their action pathways are not clearly understood. They also suffer from multiple toxic effects that limit their utility. Elucidating their action mechanisms could lead to newer agents and better understanding of the etiopathogenesis of bipolar disorder. We have expanded the study of signaling mechanisms of lithium and valproate by using Drosophila circadian locomotor activity as a robust behavioral assay that is amenable to genetic manipulations. We demonstrate that lithium affects the circadian system of Drosophila similarly to what has been reported in the mammalian studies. We show that lithium and valproate share effects on the circadian locomotor activity of Drosophila: they lengthen the period of circadian rhythms and increase arrhythmicity. Valproate exerts these effects in a weaker fashion than does lithium. We also tested the circadian alterations in multiple mutant lines of Drosophila bearing defects in the GSK-3b gene and other clock genes in response to lithium administration. We show that lithium partially rescues the shortening of circadian period when the GSK-3b gene is overexpressed only in specific circadian pacemaker neurons, thus implicating GSK-3b as a component in lithium's effect on the circadian oscillator. Moreover, lithium also lengthens the period in GSK-3b heterozygous mutants and doubletime long mutants. These results establish a basis for using Drosophila genetics to investigate more fully lithium and valproate action mechanisms.

Assessment of circadian function in fibroblasts of patients with bipolar disorder

“…We postulate that the genetically heterogeneous nature of the samples may account for the failure of detecting p-GSK3b level difference between lithiumfree bipolar and healthy controls, as we encountered when including samples from members of non-Amish family 884 in our analysis. Many studies have revealed the role of GSK3b in regulating circadian period 24,[27][28][29] and circadian phase. 25,26 Further investigation is needed to address whether the reduced p-GSK3b level in BP fibroblasts is responsible for the subtle alterations in circadian gene expression as observed in this study.…”

“…[8][9][10][11][12][13][14][15][16][17][18][19][20][21] In addition, lithium, the most effective treatment for bipolar disorder 22,23 lengthens the circadian period in mammalian cells [24][25][26] and in model organisms. [27][28][29] Lithium treatment of 293T cells leads to rapid proteosomal degradation of REV-ERBa and transcriptional activation of BMAL1, 30 which are critical components of core clock mechanism. Furthermore, suggestive evidence has recently been reported for the association of circadian gene variants including CLOCK, BMAL1, PER3 and TIMELESS with bipolar disorder.…”

Circadian genes, rhythms and the biology of mood disorders

“…Interestingly, both of these drugs have been repeatedly shown to alter the circadian period, leading to a long period in Drosophila, non-human primates, rodents and humans (Johnsson et al, 1983;Welsh and Moore-Ede, 1990;Klemfuss, 1992;Hafen and Wollnik, 1994;Dokucu et al, 2005). This effect on circadian rhythms likely involves the inhibition of GSK3β which modifies multiple members of the molecular clock (Iwahana et al, 2004;Padiath et al, 2004;Gould and Manji, 2005;Iitaka et al, 2005;Yin et al, 2006).…”

Role for theClockGene in Bipolar Disorder

“…Both of these drugs have been repeatedly shown to alter the circadian period, leading to a long period in Drosophila, nonhuman primates, rodents, and humans (Johnsson et al 1983;Welsh and Moore-Ede 1990;Klemfuss 1992;Hafen and Wollnik 1994;Dokucu et al 2005). Lithium is also able to slow the abnormally fast circadian rhythms found in most bipolar patients (Atkinson et al 1975;Kripke et al 1978).…”