0019 Assessing Genetic Variation for Effects of Lithium on Circadian Clock Period and Mortality in Fruit Flies

Abstract

Abstract Introduction Lithium is the treatment of choice for bipolar disorder, but the mechanism for its therapeutic effect remains unknown, and it has a low threshold for toxic side-effects. Bipolar disorder is cyclical disorder with periodic onsets of illness including depressive and manic episode that vary in cycle length among patients. One of lithium’s well-documented effects- a lengthened circadian clock period- is intriguing since a circadian system abnormality is a potential explanation for the cyclical nature of bipolar disorder. Fruit flies are an efficient model organism for genetic analysis of circadian clock mechanisms, but few Drosophila studies have documented circadian effects of lithium, and none have examined genetic variation. Methods We used a random sample of 13 inbred strains from the Drosophila Genetic Resource Panel and three wild-type strains to examine genetic variation for the response of circadian clock period to 20mM LiCl, and its toxicity. Adults were assayed for circadian locomotor activity in constant dark using Drosophila Activity Monitors. Circadian clock period was estimated using chi-squared periodogram. Results Among 13 inbred strains examined there is no significant effect of lithium or genetic variation for effects of lithium on circadian period, and only one inbred strain significantly lengthened circadian clock period in response to lithium. There was a significant sex difference in the response to lithium for circadian period, with an increase female and a slight decrease in males, and significant strain variation for sex-differences in circadian response to lithium. There are significant strain differences in mortality in response to lithium. All three wild-type strains significantly increased circadian period in response to lithium and varied in sensitivity to its toxicity. Conclusion Results to date suggest that the set of approximately 200 DGRP strains will be useful for investigating genetic variation for lithium toxicity and sex-differences for effects of lithium on circadian clock period. Circadian period in wild-type strains is more responsive to the period-lengthening effects of lithium, suggesting that genetic heterozygosity may play a role in the effects of lithium on circadian clock period. Support (if any) Skidmore College Biology Department and Summer Collaborative Research Program.