The Role of BTBD9 in Striatum and Restless Legs Syndrome
Restless legs syndrome (RLS) is a sensory-motor neurological disorder characterized by uncomfortable sensations in the extremities, generally at night, which is often relieved by movements. Genome-wide association studies (GWAS) have identified mutations in conferring a higher risk of RLS. Knockout...
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Published in | eNeuro Vol. 6; no. 5; p. ENEURO.0277-19.2019 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Society for Neuroscience
01.09.2019
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Subjects | |
Online Access | Get full text |
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Summary: | Restless legs syndrome (RLS) is a sensory-motor neurological disorder characterized by uncomfortable sensations in the extremities, generally at night, which is often relieved by movements. Genome-wide association studies (GWAS) have identified mutations in
conferring a higher risk of RLS. Knockout of the
homolog in mice (
) and fly results in motor restlessness and sleep disruption. Clinical studies have found RLS patients have structural and functional abnormalities in the striatum; however, whether and how striatal pathology contributes to the pathogenesis of RLS is not known. Here, we used fMRI to map regions of altered synaptic activity in basal ganglia of systematic
knock-out (KO) mice. We further dissected striatal circuits using patch-clamp electrophysiological recordings in brain slices. Two different mouse models were generated to test the effect of specific knockout of
in either striatal medium spiny neurons (MSNs) or cholinergic interneurons (ChIs) using the electrophysiological recording, motor and sensory behavioral tests. We found that
KO mice showed enhanced neural activity in the striatum, increased postsynaptic currents in the MSNs, and decreased excitability of the striatal ChIs. Knocking out
specifically in the striatal MSNs, but not the ChIs, led to rest-phase specific motor restlessness, sleep disturbance, and increased thermal sensation in mice, which are consistent with results obtained from the
KO mice. Our data establish the role of
in regulating the activity of striatal neurons. Increased activity of the striatal MSNs, possibly through modulation by the striatal ChIs, contributes to the pathogenesis of RLS. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 S.L. and H.X. contributed equally to this work. The authors declare no competing financial interests. Author contributions: S.L. and Y. Li designed research; S.L., H.X., M.P.D., Y. Liu, P.D.P., and M.F. performed research; S.L., M.P.D., Y. Liu, P.D.P., M.F., and Y. Li analyzed data; S.L., M.F., A.S.W., and Y. Li wrote the paper; F.Y. and Y. Li contributed unpublished reagents/analytic tools. This work was supported by National Institute of Health Grants R01NS082244 and R21NS065273; Restless Legs Syndrome Foundation; and the National High Magnetic Field Laboratory’s Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) Facility (National Science Foundation Cooperative Agreement DMR-1157490 and the State of Florida). |
ISSN: | 2373-2822 2373-2822 |
DOI: | 10.1523/eneuro.0277-19.2019 |