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.

Parasomnias: An Updated Review

“…Dysfunction in these structures, as well as their related neurotransmitters and pathways can result in REM sleep without atonia. [113,118,[134][135][136][137].…”

Beyond Daytime Sleepiness: Medical, Behavioral, Psychiatric, and Sleep Co-morbid Conditions Associated with Pediatric Narcolepsy

“…Note the patient has a nocturnal sleep onset REM period (REM latency <15 min) which is specific to narcolepsy type 1. These findings suggest a primary diagnosis of narcolepsy type 1 with co-morbid periodic limb movements of sleep ventral gigantocellular reticular nucleus that may also be at play [50,51].…”

Perchance to dream? Primordial motor activity patterns in vertebrates from fish to mammals: their prenatal origin, postnatal persistence during sleep, and pathological reemergence during REM sleep behavior disorder

“…Parallel with the shrinking of the neurological substrate for generating spontaneous movements during sleep, the percentage of sleep time taken up by RBM also declines progressively [5,33,72,73] largely due to the maturation of GABAergic inhibition within the caudal brainstem [45,[74][75][76][77] . As development proceeds, this motorically active phase comes to occupy less and less of total sleep time, eventually falling to a species-specific mean value which in some species accounts for only a few percent of total sleep time [2,52] .…”