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Genetic dissection of neural circuitry underlying REM sleep behavior disorder (RBD)

Wood DA, Patterson N, Fuller P, Sherman D, Saper C, Lu J (2007) Genetic dissection of neural circuitry underlying REM sleep behavior disorder (RBD). Neuroscience 2007 Abstracts 736.28/VV11. Society for Neuroscience, San Diego, CA.

Summary: REM sleep behavior disorder (RBD), a parasomnia typically manifested as dream enactment behavior, may represent an early pathophysiologic manifestation of Lewy body diseases (LBD), such as Parkinson disease and dementia with Lewy bodies. Preclinical investigation of possible underlying neural mechanisms of RBD suggests that a set of glutamatergic neurons located in the sublaterodorsal nucleus (SLD), which project to GABA/glycine interneurons in the ventral horn are responsible for atonia during REM sleep (Lu et al. 2006, A putative flip-flop switch for control of REM sleep, Nature 441, 589-94). Based upon these findings, we hypothesize that a loss of glutamate from these neurons in the SLD produces REM sleep without atonia, an animal equivalent of RBD. To assess this question, we selectively eliminated glutamate release from SLD by injecting adeno-associated virus-Cre recombinase (AAV-Cre) into the SLD of mice with lox P sites flanking exon 2 of the vesicular glutamate transporter 2 (VGLUT2) gene. In addition, we examined the role of the ventromedial medulla (VMM) in REM atonia by injecting orexin-saporin in rats and AAV-Cre into flox-VGAT (vesicular GABA/glycine transporter) and flox-VGLUT2 mice. Consistent with our hypothesis, these data show that loss of the VGLUT2 gene in the SLD produces REM sleep without atonia (walking, running and myoclonic jerking) without alteration of total amount of REM sleep. Furthermore, loss of the VGLUT2 but not the VGAT gene in the intermediate VMM results in myoclonic jerking against the background of tonic atonia during REM sleep. Based upon these observations, we propose that suppression of muscle activity during REM sleep is controlled by the activation of excitatory glutamatergic projections from the SLD (with collaterals targeting the intermediate VMM) and from the intermediate VMM, which terminate at inhibitory interneurons in the spinal cord. Collectively, this work provides novel insight into the control of muscle tone during REM sleep, which may have implications for our understanding of neurological conditions that precede the onset of neurodegenerative disease.

Related Products: Orexin-B-SAP (Cat. #IT-20)

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