Heterozygosity for the mood disorder-associated variant Gln460Arg alters P2X7 receptor function and sleep quality

Michael W. Metzger, Sandra M. Walser, Nina Dedic, Fernando Aprile-Garcia, Vladimira Jakubcakova, Marek Adamczyk, Katharine J. Webb, Manfred Uhr, Damian Refojo, Mathias V. Schmidt, Elisabeth Friess, Axel Steiger, Mayumi Kimura, Alon Chen, Florian Holsboer, Eduardo Arzt, Wolfgang Wurst, Jan M. Deussing

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


A single nucleotide polymorphism substitution from glutamine (Gln, Q) to arginine (Arg, R) at codon 460 of the purinergic P2X7 receptor (P2X7R) has repeatedly been associated with mood disorders. The P2X7R-Gln460Arg variant per se is not compromised in its function. However, heterologous expression of P2X7R-Gln460Arg together with wild-type P2X7R has recently been demonstrated to impair receptor function. Here we show that this also applies to humanized mice coexpressing both human P2X7R variants. Primary hippocampal cells derived from heterozygous mice showed an attenuated calcium uptake upon agonist stimulation. While humanized mice were unaffected in their behavioral repertoire under basal housing conditions, mice that harbor both P2X7R variants showed alterations in their sleep quality resembling signs of a prodromal disease stage. Also healthy heterozygous human subjects showed mild changes in sleep parameters. These results indicate that heterozygosity for the wild-type P2X7R and its mood disorder-associated variant P2X7R-Gln460Arg represents a genetic risk factor, which is potentially able to convey susceptibility to mood disorders.

Original languageEnglish
Pages (from-to)11688-11700
Number of pages13
JournalJournal of Neuroscience
Issue number48
StatePublished - 29 Nov 2017


  • Humanized mouse model
  • Mood disorder
  • P2X7 receptor
  • Purinergic signaling
  • Sleep
  • Stress


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