The Role of BTBD9 in the Cerebellum, Sleep-like Behaviors and the Restless Legs Syndrome. (1st August 2020)

• Record Type: Journal Article
• Authors: Lyu, Shangru; Xing, Hong; DeAndrade, Mark P.; Perez, Pablo D.; Yokoi, Fumiaki; Febo, Marcelo; Walters, Arthur S.; Li, Yuqing
• Is Part Of: Neuroscience. Volume 440(2020)
• Page Start: 85
• Page End: 96
• Publication Date: 2020-08-01
• Subjects: 12-LD normal twelve hours light and twelve hours dark condition -- Btbd9 pKO the PC-specific Btbd9 knockout mice -- CI confidence interval -- CV coefficients of variation -- DCN deep cerebellar nuclei -- EMG electromyogram -- GWAS genome-wide association studies -- MEMRI manganese-enhanced MRI -- PCs Purkinje cells -- PLM periodic leg movements -- RLS restless legs syndrome -- SLC sensory leg discomfort -- WT wildtype; sleep -- restless legs syndrome -- Btbd9 -- cerebellum -- Purkinje cells; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2020.05.021
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: The systemic Btbd9 KO mice had decreased neural activity in the cerebellum. Btbd9 KO mice had more non-tonic Purkinje cells. Tonic Purkinje cells in Btbd9 KO mice had increased spontaneous firing and intrinsic excitability. Purkinje cell-specific Btbd9 KO mice were restless at rest but had no sensory deficit. Purkinje cell-specific Btbd9 KO mice had an increased probability of waking at rest. Abstract: Recent genome-wide association studies (GWAS) have found cerebellum as a top hit for sleep regulation. Restless legs syndrome (RLS) is a sleep-related sensorimotor disorder characterized by uncomfortable sensations in the extremities, generally at night, which are often relieved by movements. Clinical studies have found that RLS patients have structural and functional abnormalities in the cerebellum. However, whether and how cerebellar pathology contributes to sleep regulation and RLS is not known. GWAS identified polymorphisms in BTBD9 conferring a higher risk of sleep disruption and RLS. Knockout of the BTBD9 homolog in mice ( Btbd9 ) and fly results in motor restlessness and sleep disruption. We performed manganese-enhanced magnetic resonance imaging on the Btbd9 knockout mice and found decreased neural activities in the cerebellum, especially in lobules VIII, X, and the deep cerebellar nuclei. Electrophysiological recording of Purkinje cells (PCs) from Btbd9 knockout mice revealed an increased number of non-tonic PCs. Tonic PCs showed increased spontaneous activity and intrinsic excitability. To further investigate the cerebellar contribution to RLS and sleep-like behaviors, we generated PC-specific Btbd9 knockout mice ( Btbd9 pKO) and performed behavioral studies. Btbd9 pKO mice showed significant motor restlessness during the rest phase but not in the active phase. Btbd9 pKO mice also had an increased probability of waking at rest. Unlike the Btbd9 knockout mice, there was no increased thermal sensation in the Btbd9 pKO. Our results indicate that the Btbd9 knockout influences the PC activity; dysfunction in the cerebellum may contribute to the motor restlessness found in the Btbd9 knockout mice.