title: Pharmacological validation of candidate causal sleep genes identified in an N2 cross.
abstract: Despite the substantial impact of sleep disturbances on human health and the many years of study dedicated to understanding sleep pathologies, the underlying genetic mechanisms that govern sleep and wake largely remain unknown. Recently, the authors completed large-scale genetic and gene expression analyses in a segregating inbred mouse cross and identified candidate causal genes that regulate the mammalian sleep-wake cycle, across multiple traits including total sleep time, amounts of rapid eye movement (REM), non-REM, sleep bout duration, and sleep fragmentation. Here the authors describe a novel approach toward validating candidate causal genes, while also identifying potential targets for sleep-related indications. Select small-molecule antagonists and agonists were used to interrogate candidate causal gene function in rodent sleep polysomnography assays to determine impact on overall sleep architecture and to evaluate alignment with associated sleep-wake traits. Significant effects on sleep architecture were observed in validation studies using compounds targeting the muscarinic acetylcholine receptor M3 subunit (Chrm3) (wake promotion), nicotinic acetylcholine receptor alpha4 subunit (Chrna4) (wake promotion), dopamine receptor D5 subunit (Drd5) (sleep induction), serotonin 1D receptor (Htr1d) (altered REM fragmentation), glucagon-like peptide-1 receptor (Glp1r) (light sleep promotion and reduction of deep sleep), and calcium channel, voltage-dependent, T type, alpha 1I subunit (Cacna1i) (increased bout duration of slow wave sleep). Taken together, these results show the complexity of genetic components that regulate sleep-wake traits and highlight the importance of evaluating this complex behavior at a systems level. Pharmacological validation of genetically identified putative targets provides a rapid alternative to generating knock out or transgenic animal models, and may ultimately lead towards new therapeutic opportunities.
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Brunner
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.forename: Joshua
authors.initials: J
authors.lastname: Millstein
authors.forename: Susan
authors.initials: S
authors.lastname: Garson
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Binns
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.forename: Alan T
authors.initials: AT
authors.lastname: Savitz
authors.forename: He S
authors.initials: HS
authors.lastname: Yang
authors.forename: Karrie
authors.initials: K
authors.lastname: Fitzpatrick
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Owens
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Webber
authors.forename: Martha H
authors.initials: MH
authors.lastname: Vitaterna
authors.forename: Andrew
authors.initials: A
authors.lastname: Kasarskis
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.forename: Fred
authors.initials: F
authors.lastname: Turek
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type / Q000235:genetics; D020907:Calcium Channels, Q-Type / Q000235:genetics; D003433:Crosses, Genetic; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D043587:Receptor, Muscarinic M3 / Q000235:genetics; D050641:Receptors, Dopamine D5 / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics; D012890:Sleep / Q000187:drug effects* / Q000235:genetics*; D012893:Sleep Wake Disorders / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism
chemical_list: D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D043587:Receptor, Muscarinic M3; D050641:Receptors, Dopamine D5; D011978:Receptors, Nicotinic; C493607:Drd5 protein, rat
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