Protective roles of the lithium-inducible SLC6 transporter in lithium's adverse effects: Insights from Drosophila genetics - PROJECT SUMMARY Lithium, a small alkali metal, has unique and complex effects on the nervous system. Known for its protective and proliferative effects on neurons, lithium has long been the primary treatment for bipolar disorder and also shows potential for treating a variety of other nervous system disorders. However, the mechanisms behind its therapeutic benefits and side effects remain largely unknown. Gaining a comprehensive understanding of the molecular and cellular mechanisms that underlie lithium's biological actions is both neurobiologically significant and essential for maximizing its therapeutic potential while minimizing adverse effects. This project focuses on lithium's adverse effects, aiming to identify the underlying biological processes through Drosophila genetics and physiology. The central hypothesis is that the metabolism of amino acids, particularly proline metabolism, plays a crucial role in controlling susceptibility to lithium. Supporting this hypothesis, findings have shown that a putative proline transporter, known as the Lithium-inducible SLC6 transporter (List), is significantly upregulated following lithium treatment. Furthermore, loss-of-function mutations in List result in marked increase in sensitivity to lithium's adverse effects, along with reduced proline levels following lithium treatment. To test the hypothesis, the project will pursue three specific aims: (1) Elucidate the role of proline metabolism in lithium susceptibility. The mouse proline transporter, which is a putative ortholog of Drosophila List, will be assessed for its potential to reduce the mortality in List mutants exposed to lithium. Additionally, genetic variants involved in proline synthesis and degradation will be analyzed to understand the unique roles of proline metabolism in response to lithium. (2) Determine the effects of List and lithium on neural function. Semi-intact neuromuscular junction (NMJ) preparations will be used to examine how specific neurophysiological properties of nerves, synapses, and muscles are altered by List manipulations and lithium treatment. (3) Identify additional genes that influence lithium's adverse effects. Genome-wide association studies will be conducted to identify genes essential for the molecular and cellular processes involved in response to lithium treatment. This work will utilize the Drosophila Genetic Reference Panel, a very powerful collection of genetically and phenotypically diverse inbred fly strains with fully sequenced genomes, under both normal and lithium-sensitized conditions. Given the extensive conservation of fundamental biological processes between Drosophila and mammals, insights gained from this project are expected to illuminate mechanisms underlying lithium's effects in humans. This research will establish a strong foundation for future studies exploring the detailed mechanisms of lithium-responsive biological processes through Drosophila genetics and physiology. Furthermore, collaboration with experts in mammalian biology will support the investigation of these findings' relevance and applicability to mammalian systems. This comprehensive approach aims to significantly enhance our understanding of lithium's beneficial and adverse effects, ultimately contributing to improved treatment options for various nervous system dysfunctions. .
