Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder

Abstract

Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in muscle atonia during PS and highlight a candidate brain region that can be susceptible to α-synuclein-dependent degeneration in RBD patients.

Impaired glycinergic transmission in hyperekplexia: a model of parasomnia overlap disorder

“…Recent studies in mice and rats demonstrated the major role of inhibitory GABA/glycinergic synapses in motor pathways of the brainstem. Genetic inactivation in GABA/glycine neurotransmission in the ventromedial medulla disrupts muscle atonia during REM sleep and triggers abnormal behaviors without any effect during waking and slow‐wave sleep . Transgenic mice with deficient glycine and GABA‐A receptor function exhibited increased motor activity during NREM and REM sleep, NREM myoclonic jerks, sleep fragmentation, and increased phasic but normal tonic motor activities in REM sleep .…”

“…These mice also presented myoclonic jerks during non‐REM (NREM) sleep and large sleep fragmentation. Another model of RBD was recently reported in rats after selective inactivation of the GABA/glycinergic transmission in the ventral medial medulla . The precise role of impaired GABA/glycine transmission in the pathophysiology of human RBD remains unknown …”

Reticulospinal Systems for Tuning Motor Commands

“…A proportion of RSNs descending in the MLF are inhibitory (Du Beau et al, 2012 ), and approximately 20% of RS synaptic contacts on propriospinal and spinal commissural interneurons in the lumbar spinal cord are inhibitory (Mitchell et al, 2016 ). Recently it has been shown that glycinergic neurons located in the GRN descend to the lumbar spinal cord (Valencia Garcia et al, 2018 ; vide infra ).…”

“…Both of these targets contribute to sleep atonia, but whether the direct descending command from the GRN is inhibitory and/or whether its inhibitory effects are mediated by spinal interneurons is not clear (Fuller et al, 2007 ; Arrigoni et al, 2016 ). Recent evidence, however, suggests that there is descending inhibitory input that produces sleep atonia (Valencia Garcia et al, 2018 ).…”

Animal Model for Prodromal Parkinson’s Disease

“…In autopsy brains of PD patients who developed PD and dementia with Lewy bodies (DLB) preceded by idiopathic RBD, LBs were identified in the pedunculopontine tegmental nucleus (PPN), locus coeruleus/subcoeruleus complex, and gigantocellular reticular nucleus in medulla oblongata [46]. These regions are considered part of the neural circuit controlling atonia during REM sleep in animal experiments [6,47,48] and thus responsible for RBD. In this way the pathological progression of PD largely follows Braak's staging.…”