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Investigation of dopaminergic signalling in Meis homeobox 1 (Meis1) deficient mice as an animal model of restless legs syndrome.

J Sleep Res. 2021 May 18:e13311. doi: 10.1111/jsr.13311. Epub ahead of print. PMID: 34008292.

Authors/Editors: Cathiard L, Fraulob V, Lam DD, Torres M, Winkelmann J, Krężel W.
Publication Date: 2021

Abstract

Restless legs syndrome (RLS) is a common neurological disorder in which sensorimotor symptoms lead to sleep disturbances with substantial impact on life quality. RLS is caused by a combination of genetic and environmental factors, and Meis homeobox 1 (MEIS1) was identified as the main genetic risk factor. The efficacy of dopaminergic agonists, including dopamine D2 receptor (DRD2) agonists, for treating RLS led to the hypothesis of dopaminergic impairment. However, it remains unclear whether it is directly involved in the disease aetiology and what the role of MEIS1 is considering its developmental and postnatal expression in the striatum, a critical structure in motor control. We addressed the role of MEIS1 in striatal dopaminergic signalling in Meis1+/- mice, a valid animal model of RLS, and in Meis1Drd2 -/- mice carrying a somatic null mutation of Meis1 in Drd2+ neurones. Motor behaviours, pharmacological exploration of DRD2 signalling, and quantitative analyses of DRD2+ and DRD1+ expressing neurones were investigated. Although Meis1+/- mice displayed an RLS-like phenotype, including motor hyperactivity at the beginning of the rest phase, no reduction of dopaminoceptive neurones was observed in the striatum. Moreover, the null mutation of Meis1 in DRD2+ cells did not lead to RLS-like symptoms and dysfunction of the DRD2 pathway. These data indicate that MEIS1 does not modulate DRD2-dependent signalling in a cell-autonomous manner. Thus, the efficiency of D2 -like agonists may reflect the involvement of other dopaminergic receptors or normalisation of motor circuit abnormalities downstream from defects caused by MEIS1 dysfunction.

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