Lucae S, Salyakina D, Barde N, Harvey M, Gagné B, Labbé M et al.. P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder. Hum Mol Genet 15: 2438-2445

The Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany.
Human Molecular Genetics (Impact Factor: 6.39). 09/2006; 15(16):2438-45. DOI: 10.1093/hmg/ddl166
Source: PubMed


The P2RX7 gene is located within a region on chromosome 12q24.31 that has been identified as a susceptibility locus for affective disorders by linkage and association studies. P2RX7 is a purinergic ATP-binding calcium channel expressed in neurons as well as in microglial cells in various brain regions. We investigated 29 single nucleotide polymorphisms (SNPs) within the P2RX7 gene and adjacent genes in a sample of 1000 German Caucasian patients suffering from recurrent major depressive disorder (MDD). These were contrasted with diagnosed healthy Caucasian controls from the same population (n=1029). A non-synonymous coding SNP in the P2RX7 gene (rs2230912), previously found to be associated with bipolar disorder, was significantly associated (P=0.0019) with MDD. This polymorphism results in an amino acid exchange in the C-terminal cytosolic domain of the P2RX7 channel protein, suggesting that the observed P2RX7 polymorphism might play a causal role in the development of depression.

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    • "A similar gain of function of P2X7R in formatting microglia responsiveness has been observed after ischemia (Franke et al., 2004), MS (Yiangou et al., 2006), prion disease (Takenouchi et al., 2007), PD (Marcellino et al., 2010) or upon status epilepticus (Rappold et al., 2006; Avignone et al., 2008; Kim et al., 2009; Choi et al., 2012; Engel et al., 2012), where P2X7R blockade/deletion reduces seizure severity during status epilepticus (Solle et al., 2001; Engel et al., 2012; Jimenez-Pacheco et al., 2013). P2X7R have also been linked to psychiatric disorders, as heralded by the association of P2X7R polymorphisms with major depression (Lucae et al., 2006; Hejjas et al., 2009) and by the anti-depressive behavior of P2X7R KO mice (Basso et al., 2009; Csölle et al., 2013), in line with the ability of IL-1β to induce depression-like behavioral changes (Pollak and Yirmiya, 2002; Anisman et al., 2005). Besides this major role on overactivation of microglia, P2X7R are also up-regulated in reactive astrocytes and in neurons in the diseased brain (Franke et al., 2004; Doná et al., 2009; Engel et al., 2012). "
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    Frontiers in Neuroscience 04/2015; 9. DOI:10.3389/fnins.2015.00148 · 3.66 Impact Factor
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    • "Recent evidence from genetic and clinical studies supports the involvement of purinergic system in the pathophysiology of BD and recurrent major depression, with therapeutic implications (Barden et al., 2006; Lucae et al., 2006; Zarate and Manji, 2008; McQuillin et al., 2009; Kesebir et al., 2013). Increased serum UA levels in manic episodes might be the result of the increased purinergic turnover, Contents lists available at ScienceDirect journal homepage: "
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    • "chromosome that carries the P2X7 gene) and mood disturbance. In the case of unipolar depression , Lucae et al. (2006) "
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    ABSTRACT: A number of studies have identified that mutations in the P2X7 receptor occur with a significantly higher incidence in individuals with major depression. Consistent with these findings, a number of preclinical studies have identified that mice in which the P2X7 receptor has been deleted exhibit a higher level of resilience-like behaviour to acutely aversive situations. At present, however, no studies have examined changes in P2X7 receptor expression in otherwise healthy animals exposed to persistently stressful situations. This is significant as several lines of evidence have demonstrated that it is exposure to persistently aversive, rather than acutely aversive, situations that is associated with the emergence of mood disturbance. Accordingly, the objective of the current study was to examine whether chronic exposure to restraint stress was associated with alterations in the expression of P2X7 within the hippocampal formation. The study involved three principal groups: acute stress (1 session), chronic stress (21 sessions, 1 per day) and a chronic stress with recovery group (21 sessions, 1 per day followed by 7 days of no stress) and appropriate control groups. The results of the analysis indicate that all forms of stress, regardless of the duration, provoked a reduction in P2X7 receptor expression. Comparative analysis on normalised data indicated that the magnitude of the P2X7 reduction was significantly greater in the chronic stress relative to the acute stress group. We additionally found that there was a gradual rebound in P2X7 expression, in two of nine regions examined, in animals that were allowed to recover for 7 days following the final stress session. Collectively, these findings provide the first evidence that exposure to chronic restraint stress produces a pronounced and relatively persistent suppression of the P2X7 receptor within the hippocampus.
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