Drosophila Shaker mutant as model for studying the neurobiology of sleep and mood disorders: effects of lithium and memantine on protein expression, activity and sleep

Clinical studies show circadian rhythm dysfunctions involvement in mood disorders and research is focusing on sleep disorders as predictor of bipolar disorder (BP). Its pathophysiology involves ion dysregulation and acute manic patients showed increased glutamate levels. Lithium, although its exact mechanism is still poorly under- stood, remains the first choice for treating mania in BP. Preclinical studies however have demonstrated the efficacy of memantine a non-competitive NMDA receptor antagonist, as mood-stabilizing drug in patients lithium resistant. Hyperexcitability, motor hyperactivity and reduced sleep characterized the Drosophila melanogaster Shaker mutant ( Sh ). These flies, carrying a mutation in the K + Shaker channel alpha-subunit (the invertebrate counterpart of Kv1), present a delayed membrane repolarization causing severe phenotypical aberrations. We propose such mutant flies as a model to study the response to lithium and memantine exploring the effect on motor activity and sleep patterns. Sh mutants and their control lines have been fed a diet containing lithium or memantine at different concentrations for 3 weeks. Lifespan, twenty-four hour motor activity (DAMS, Trikinetics) and sleep have been measured at the end of treatment. Brains from all groups have been processed for Western Blot analysis. Memantine affects Sh mutants sleep pattern improving quality and rhythm, reduces activity and increase life span. Western blot analysis reveals increased NMDAR1 protein expression in Sh mutants, restored to normal levels after memantine. Preliminary results in lithium fed flies showed some effects on motor activity and sleep. Our model is a promising tool and a valid alternative to rodents models of human diseases.