We are such stuff as dreams are made on, and that stuff includes Chrm1 and Chrm3, genes for a pair of acetylcholine receptors. According to a new study based at the RIKEN Center for Biosystems Dynamics Research in Japan, these genes are necessary for rapid eye movement (REM) sleep.
To uncover the molecular mechanisms behind REM sleep, the RIKEN-led scientific team experimented with cholinergic neurons in a mouse model. Such neurons are studded with acetylcholine receptors, which previous studies have implicated in the regulation of REM sleep.
The scientists synaptically inhibited these neurons to identify a neuron population that was essential to sleep. Then the scientists used the CRISPR gene editing technique to systematically disable acetylcholine receptor genes. When the scientists knocked out both the Chrm1 and Chrm3 genes, levels of REM sleep dropped to levels that were almost undetectable.
Details of this work appeared in the journal Cell Reports, in an article titled, “Muscarinic Acetylcholine Receptors Chrm1 and Chrm3 Are Essential for REM Sleep.” This article extends previous studies, which implicated the neurotransmitter acetylcholine in the regulation of REM sleep but did not go so far as to clarify which acetylcholine receptor or receptors were directly involved.
“We demonstrate that synaptic inhibition of TrkA+ cholinergic neurons causes a severe short-sleep phenotype and that sleep reduction is mostly attributable to a shortened sleep duration in the dark phase,” the article’s authors wrote. “Subsequent comprehensive knockout of acetylcholine receptor genes by the triple-target CRISPR method reveals that a similar short-sleep phenotype appears in the knockout of two Gq-type acetylcholine receptors Chrm1 and Chrm3.”
Reduction of sleep duration in mice was mostly attributable to the reduced duration of NREM sleep, indicating that cholinergic regulation is also important for NREM sleep. The authors, however, also cited earlier research indicating that impaired REM sleep might also reduce the duration of NREM sleep. In support of this possibility, the authors offered this mechanistic observation: “Loss of either Chrm1, Chrm3, or both resulted in reduced, fragmented, and diminished REM sleep, respectively.”
Chrm1 and Chrm3, are widely distributed in distinct brain regions. When both genes were knocked out, mice failed almost entirely to experience REM sleep, but survived nonetheless.
“The surprising finding that mice are viable despite the almost complete loss of REM sleep will allow us to rigorously verify whether REM sleep plays a crucial role in fundamental biological functions such as learning and memory,” says RIKEN researcher Yasutaka Niwa, the co-first author of this article.
These findings strongly suggest that these two receptors are essential for sleep regulation, especially REM sleep, and function in different ways. “The discovery that Chrm1 and Chrm3 play a key role in REM sleep opens the way to studying its underlying cellular and molecular mechanisms and will eventually allow us to define the state of REM sleep, which has been paradoxical and mysterious since its original report,” comments Hiroki Ueda, the study’s senior author and a researcher affiliated with RIKEN and the University of Tokyo.