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Heterozygosity for the Mood Disorder-Associated Variant Gln460Arg Alters P2X7 Receptor Function and Sleep Quality

By Michael W. Metzger, Sandra M. Walser, Nina Dedic, Fernando Aprile García, 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 Simon Arzt, Wolfgang Wurst and Jan M. Deussing

Abstract

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.Fil: Metzger, Michael W.. Max Planck Institut Fur Psychiatrie; AlemaniaFil: Walser, Sandra M.. Max Planck Institut Fur Psychiatrie; AlemaniaFil: Dedic, Nina. Max Planck Institut Fur Psychiatrie; AlemaniaFil: Aprile García, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Jakubcakova, Vladimira. Max Planck Institut Fur Psychiatrie; AlemaniaFil: Adamczyk, Marek. Max Planck Institut Fur Psychiatrie; AlemaniaFil: Webb, Katharine J.. Max Planck Institut Fur Psychiatrie; AlemaniaFil: Uhr, Manfred. Max Planck Institut Fur Psychiatrie; AlemaniaFil: Refojo, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Schmidt, Mathias V.. Max Planck Institut Fur Psychiatrie; AlemaniaFil: Friess, Elisabeth. Max Planck Institut Fur Psychiatrie; AlemaniaFil: Steiger, Axel. Max Planck Institut Fur Psychiatrie; AlemaniaFil: Kimura, Mayumi. Max Planck Institut Fur Psychiatrie; AlemaniaFil: Chen, Alon. Max Planck Institut Fur Psychiatrie; Alemania. Weizmann Institute of Science; IsraelFil: Holsboer, Florian. Max Planck Institut Fur Psychiatrie; AlemaniaFil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Wurst, Wolfgang. Institute of Developmental Genetics; Alemania. Technische Universität München-Weihenstephan; Alemania. German Center for Neurodegenerative Diseases; Alemania. Universität München; AlemaniaFil: Deussing, Jan M.. Max Planck Institut Fur Psychiatrie; Alemani

Topics: HUMANIZED MOUSE MODEL, MOOD DISORDER, P2X7 RECEPTOR, PURINERGIC SIGNALING, SLEEP, STRESS, Inmunología, Medicina Básica, CIENCIAS MÉDICAS Y DE LA SALUD
Publisher: 'Society for Neuroscience'
Year: 2017
DOI identifier: 10.1523/JNEUROSCI.3487-16.2017
OAI identifier: oai:ri.conicet.gov.ar:11336/55204
Provided by: CONICET Digital
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