title: Impaired GABA and glycine transmission triggers cardinal features of rapid eye movement sleep behavior disorder in mice.
abstract: Rapid eye movement (REM) sleep behavior disorder (RBD) is a neurological disease characterized by loss of normal REM motor inhibition and subsequent dream enactment. RBD is clinically relevant because it predicts neurodegenerative disease onset (e.g., Parkinson's disease) and is clinically problematic because it disrupts sleep and results in patient injuries and hospitalization. Even though the cause of RBD is unknown, multiple lines of evidence indicate that abnormal inhibitory transmission underlies the disorder. Here, we show that transgenic mice with deficient glycine and GABA transmission have a behavioral, motor, and sleep phenotype that recapitulates the cardinal features of RBD. Specifically, we show that mice with impaired glycine and GABA(A) receptor function exhibit REM motor behaviors, non-REM muscle twitches, sleep disruption, and EEG slowing--the defining disease features. Importantly, the RBD phenotype is rescued by drugs (e.g., clonazepam and melatonin) that are routinely used to treat human disease symptoms. Our findings are the first to identify a potential mechanism for RBD--we show that deficits in glycine- and GABA(A)-mediated inhibition trigger the full spectrum of RBD symptoms. We propose that these mice are a useful resource for investigating in vivo disease mechanisms and developing potential therapeutics for RBD.
authors.affiliation: Systems Neurobiology Laboratory, Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brooks
authors.forename: John H
authors.initials: JH
authors.lastname: Peever
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002492:Central Nervous System Depressants / Q000494:pharmacology / Q000627:therapeutic use; D002998:Clonazepam / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004569:Electroencephalography; D018757:GABA Modulators / Q000494:pharmacology / Q000627:therapeutic use; D005998:Glycine / Q000502:physiology*; D008550:Melatonin / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D020187:REM Sleep Behavior Disorder / Q000188:drug therapy / Q000503:physiopathology*; D012890:Sleep / Q000235:genetics*; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D002492:Central Nervous System Depressants; D018757:GABA Modulators; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; D008550:Melatonin; D005998:Glycine