title: Genetic inactivation of glutamate neurons in the rat sublaterodorsal tegmental nucleus recapitulates REM sleep behaviour disorder.
abstract: SEE SCHENCK AND MAHOWALD DOI101093/AWW329 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Idiopathic REM sleep behaviour disorder is characterized by the enactment of violent dreams during paradoxical (REM) sleep in the absence of normal muscle atonia. Accumulating clinical and experimental data suggest that REM sleep behaviour disorder might be due to the neurodegeneration of glutamate neurons involved in paradoxical sleep and located within the pontine sublaterodorsal tegmental nucleus. The purpose of the present work was thus to functionally determine first, the role of glutamate sublaterodorsal tegmental nucleus neurons in paradoxical sleep and second, whether their genetic inactivation is sufficient for recapitulating REM sleep behaviour disorder in rats. For this goal, we first injected two retrograde tracers in the intralaminar thalamus and ventral medulla to disentangle neuronal circuits in which sublaterodorsal tegmental nucleus is involved; second we infused bilaterally in sublaterodorsal tegmental nucleus adeno-associated viruses carrying short hairpin RNAs targeting Slc17a6 mRNA [which encodes vesicular glutamate transporter 2 (vGluT2)] to chronically impair glutamate synaptic transmission in sublaterodorsal tegmental nucleus neurons. At the neuroanatomical level, sublaterodorsal tegmental nucleus neurons specifically activated during paradoxical sleep hypersomnia send descending efferents to glycine/GABA neurons within the ventral medulla, but not ascending projections to the intralaminar thalamus. These data suggest a crucial role of sublaterodorsal tegmental nucleus neurons rather in muscle atonia than in paradoxical sleep generation. In line with this hypothesis, 30 days after adeno-associated virus injections into sublaterodorsal tegmental nucleus rats display a decrease of 30% of paradoxical sleep daily quantities, and a significant increase of muscle tone during paradoxical sleep concomitant to a tremendous increase of abnormal motor dream-enacting behaviours. These animals display symptoms and behaviours during paradoxical sleep that closely mimic human REM sleep behaviour disorder. Altogether, our data demonstrate that glutamate sublaterodorsal tegmental nucleus neurons generate muscle atonia during paradoxical sleep likely through descending projections to glycine/GABA premotor neurons in the ventral medulla. Although playing a role in paradoxical sleep regulation, they are, however, not necessary for inducing the state itself. The present work further validates a potent new preclinical REM sleep behaviour disorder model that opens avenues for studying and treating this disabling sleep disorder, and advances potential regions implicated in prodromal stages of synucleinopathies such as Parkinson's disease.
authors.affiliation: Neuroscience Research Center of Lyon (CRNL), CNRS UMR 5292, INSERM U1028, SLEEP Team, Lyon, France.|Lyon1 Claude Bernard University, Lyon, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Valencia Garcia
authors.affiliation: Neuroscience Research Center of Lyon (CRNL), CNRS UMR 5292, INSERM U1028, SLEEP Team, Lyon, France.|Lyon1 Claude Bernard University, Lyon, France.
authors.forename: Paul-Antoine
authors.initials: PA
authors.lastname: Libourel
authors.affiliation: International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Michael
authors.initials: M
authors.lastname: Lazarus
authors.affiliation: International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Daniela
authors.initials: D
authors.lastname: Grassi
authors.affiliation: Neuroscience Research Center of Lyon (CRNL), CNRS UMR 5292, INSERM U1028, SLEEP Team, Lyon, France.|Lyon1 Claude Bernard University, Lyon, France.
authors.forename: Pierre-Hervé
authors.initials: PH
authors.lastname: Luppi
authors.affiliation: Neuroscience Research Center of Lyon (CRNL), CNRS UMR 5292, INSERM U1028, SLEEP Team, Lyon, France patrice.fort@univ-lyon1.fr.|Lyon1 Claude Bernard University, Lyon, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Fort
mesh_terms: D000818:Animals; D002452:Cell Count; D002772:Cholera Toxin / Q000493:pharmacokinetics; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D050582:Excitatory Amino Acid Transporter 5 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism*; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000502:physiology*; D066250:Pretectal Region / Q000378:metabolism / Q000473:pathology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D020187:REM Sleep Behavior Disorder / Q000209:etiology / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012892:Sleep Deprivation / Q000150:complications; D013057:Spectrum Analysis; D013266:Stilbamidines / Q000493:pharmacokinetics
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D050582:Excitatory Amino Acid Transporter 5; D050487:Glycine Plasma Membrane Transport Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C493269:Slc6a5 protein, rat; D013266:Stilbamidines; D018698:Glutamic Acid; D002772:Cholera Toxin
keywords: Parkinson; REM sleep; REM sleep Behaviour Disorder; SLD; glutamate