Characterization of Meis1 mutant mice and implications in restless legs syndrome and other sleep disorders

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Restless leg syndrome (RLS) is a sleep-related sensorimotor neurological disease affecting up to 10% of the general population. Characteristic symptoms of RLS include an urge for patients to move their legs often accompanied by, or felt to be caused by, uncomfortable sensations in the legs. The pathophysiology of RLS is unclear. Genome-wide association studies (GWAS) of RLS patients have identified up to 19 loci that are involved in RLS. The most significant association is within the MEIS1 gene. GWAS has also linked MEIS1 with insomnia, which can be caused by RLS. Besides, MEIS1 is found to be associated with accelerometer-derived sleep traits, including sleep duration, efficiency, and timing. MEIS1 codes for a homeobox protein thought to be a transcriptional factor. A MEIS1 intronic haplotype linked to RLS risk is associated with decreased protein expression, suggesting the variant causes haploinsufficiency. Therefore, heterozygous Meis1 knockout (Meis1 KO) mice can be used as a potential model for human RLS and other sleep disorders. We have tested the Meis1 KO mice for sleep and other RLS-like phenotypes. Our strong preliminary data showed that Meis1 KO mice were hyperactive and had an increased probability of waking especially during the rest phase. In addition, Meis1 KO mice had increased striatal DA turnover, decreased striatal tyrosine hydroxylase and abnormal firing of striatal cholinergic interneurons. Both dopaminergic and striatal cholinergic systems have been shown to be involved in sleep regulation. However, the underlying mechanisms of their involvement in RLS and sleep are still unclear. The broad, long-term objective of our research is to use the Meis1 KO mice to understand the pathophysiology of RLS, insomnia and other sleep disorders, and therefore to develop novel experimental therapeutics to treat these diseases. The specific goal of this application is to determine the contribution of the striatal dopaminergic and cholinergic systems to RLS-like phenotypes and sleep regulation, We hypothesize that the changes in dopaminergic and cholinergic systems are cell-autonomous effects of Meis1 haploinsufficiency and they contribute differently to RLS-like phenotypes and sleep regulation. We plan to test our hypothesis with the following Specific Aims: 1. To test the hypothesis that the dopaminergic system contributes to RLS and sleep regulation, we will create dopaminergic neuron-specific Meis1 KO mice and perform comprehensive behavioral, biochemical, anatomical, and electrophysiological tests. 2. To test the hypothesis that the striatal cholinergic system contributes to RLS and sleep regulation, we will create cholinergic neuron-specific Meis1 KO mice and perform comprehensive tests outlined in Aim 1. The successful completion of the above Aims will determine how MEIS1 haploinsufficiency influences the dopaminergic system and why dopamine agonists can be used to treat RLS. In addition, the study can help improve the current understanding of the pathophysiology of RLS and other sleep disorders, including insomnia. The results can potentially aid in the development of novel therapeutics and better treatment strategies for patients.