Identification of genes involved in the lithium-responsive neurological process

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DESCRIPTION (provided by applicant): Lithium has been used as the highly effective therapy for bipolar disorder (BPD), a chronic and disabling mental illness that affects more than 2 million people in the US. Understanding the therapeutic action of lithium would provide important insight into the etiology and pathophysiology of BPD, and help to develop better treatment for this serious disease. The goal of the proposed research is to elucidate molecular and cellular mechanisms involved in the lithium-responsive neurological pathway using the fruit fly as a model organism. A Drosophila mutant Shudderer (Shu) is an X-linked dominant mutant that exhibits various neurological phenotypes, including hyperactivity, uncoordinated movements, sporadically occurring jerks and anesthesia-induced seizure. Interestingly, many of these phenotypes are greatly suppressed by lithium with the internal concentrations used for treatment of BPD patients. In addition, Shu may functionally interact with the glycogen synthase kinase 3 gene that has been implicated in the lithium therapeutic action. Specific aims of this proposal are to: 1) identify the Shu gene and determine the molecular nature of the Shu mutation and; 2) identify genes that functionally interact with Shu. To accomplish the Aim-1, the location of the Shu mutation will be mapped in a small genomic region (<50 kb) using a high-resolution recombination-based mapping approach with molecularly defined P element insertions. The Shu gene will be identified and the molecular nature of the mutation will be determined by sequencing the genomic DNA isolated from the fully isogenized Shu mutant flies. Transformants carrying either a wild type or a mutant form of the Shu gene will be used to confirm the identity of the gene. For Aim-2, the molecularly defined deficiencies and mutations will be introduced into the Shu mutant background to identify suppressors and enhancers for the Shu mutation. The research proposed in this application is significant, because studies of the Shu mutant are expected to provide novel knowledge of genetic components underlying the lithium-responsive process in the nervous system. Based on the fact that the fundamental molecular and cellular mechanisms are well conserved between the fruit fly and vertebrates, the findings are also expected to lead to the recognition of uncharacterized players or processes responsible for the lithium action in the vertebrates, which would open up the future possibility to develop novel and improved therapies for BPD.