Shudderer (Shu) is an X-linked dominant mutation in Drosophila melanogaster identified more than 40 years ago. A previous study showed that Shu caused spontaneous tremors and defects in reactive climbing behavior, and that these phenotypes were significantly suppressed when mutants were fed food containing lithium, a mood stabilizer used in the treatment of bipolar disorder (Williamson, 1982). This unique observation suggested that the Shu mutation affects gene(s) involved in lithium-responsive neurobiological processes. In the present study, we identified Shu as a novel mutant allele of the voltage-gated sodium (Nav) channel gene paralytic (para). Given that hypomorphic para alleles and RNAi-mediated para knockdown reduced the severity of Shu phenotypes, Shu was classified as a para hypermorphic allele. We also demonstrated that lithium could improve the behavioral abnormalities displayed by other Nav mutants, including a fly model of the human generalized epilepsy with febrile seizures plus. Our electrophysiological analysis of Shu showed that lithium treatment did not acutely suppress Nav channel activity, indicating that the rescue effect of lithium resulted from chronic physiological adjustments to this drug. Microarray analysis revealed that lithium significantly alters the expression of various genes in Shu, including those involved in innate immune responses, amino acid metabolism and oxidation-reduction processes, raising the interesting possibility that lithium-induced modulation of these biological pathways may contribute to such adjustments. Overall, our findings demonstrate that Nav channel mutants in Drosophila are valuable genetic tools for elucidating the effects of lithium on the nervous system in the context of neurophysiology and behavior.
Significance Statement: The alkaline metal lithium has been used as one of the most effective mood-stabilizing agents for BPD for over 60 years. Although a number of molecular targets for lithium have been proposed, the neural mechanisms underlying lithium action still remain unclear. Here we show that lithium treatment significantly reduced the severity of seizure-like hyperexcitability displayed by hypermorphic alleles of the Drosophila Nav channel gene. Our studies indicate that suppression of mutant phenotypes is achieved through lithium-induced physiological adjustments, leading to compensation of defects caused by mutated Nav channels. These findings provide novel insight into the effects of the mood-stabilizing agent lithium on neural function and behavior and may ultimately contribute to a clearer understanding of lithium-responsive disorders in humans.
The authors declare no conflict of interest.
This study was supported by NIH grants (R03MH62684/R01MH085081 to T.K., R01GM088804/R01GM080255 to C.-F.W., F31MH081788 to G.K., F31NS082001 to A.I., and T32NS045549 to P.L.).