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

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. Depression and bipolar disorder are the most common mood disorders. The P2X7 receptor (P2X7R) regulates many cellular functions. Its polymorphic variant Gln460Arg has repeatedly been associated with mood disorders. Genetically engineered mice, with human P2X7R, revealed that heterozygous mice (i.e., they coexpress the disease-associated Gln460Arg variant together with its normal version) have impaired receptor function and showed sleep disturbances. Human participants with the heterozygote genotype also had subtle alterations in their sleep profile. Our findings suggest that altered P2X7R function in heterozygote individuals disturbs sleep and might increase the risk for developing mood disorders.

18F-JNJ-64413739, a Novel PET Ligand for the P2X7 Ion Channel: Radiation Dosimetry, Kinetic Modeling, Test-Retest Variability, and Occupancy of the P2X7 Antagonist JNJ-54175446

“…So far, the influence of genetic polymorphisms on receptor expression levels or tracer binding properties are unknown. Interestingly, several human genetic studies have associated the highly polymorphic P2X7R gene with mood disorders (35)(36)(37), and some of these mutations have been linked to the modulation of P2X7 channel function in vitro (38). Therefore, whether P2X7R polymorphisms also may account for part of the variability of baseline P2X7 expression and therefore may render between-group comparisons of baseline P2X7 availability more challenging needs to be further investigated.…”

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

“…Another factor of insecurity inherent to the P2X7Rdeficient mice is that with the two types used routinely for experimentation, some splice variants of the P2RX7 gene escape inactivation (Bartlett et al, 2014;Sperlágh and Illes, 2014). Experiments with a recently generated conditional humanized P2X7R-deficient mouse, supposed to be devoid of active splice variants of the receptor, could be helpful in this respect (Metzger et al, 2017b).…”

Use of Humanized Mouse Models to Investigate the Roles of Purinergic Signaling in Inflammation and Immunity

“…The first involves the expression of specific human gene products within mice including cases in which a given mouse gene is replaced by the human ortholog ( Stripecke et al, 2020 ). Examples of mice incorporating transgenes of human purinergic molecules include the overexpression of human CD39 ( ENTPD1 ) ( Dwyer et al, 2004 ), as well as the substitution of the mouse gene with the corresponding human gene for the adenosine A 3 receptor ( ADORA3 ) ( Yamano et al, 2005 ), P2X7 receptor ( P2RX7 ) ( Metzger et al, 2017a ) or a Gln460Arg P2X7 receptor variant ( Metzger et al, 2017b ). The second group of humanized mice, so called xenogeneic mouse models, involves the transfer of human cells into mice, which are typically immunodeficient ( Stripecke et al, 2020 ).…”