The absence of P2X7 receptors (P2rx7) on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice

“The perchloric anion was precipitated by addition of 1 M KOH, removed by centrifugation and the protein content of the pellet was determined according to the method of Lowry et al. (1951).”

“The complete microarray expression data are deposited at NCBI’s Gene Expression Omnibus (Edgar et al. 2002) through GEO series accession number GSE21218 (http:// www.”

“Circulating cytokines, including IL-1b, are important mediators of depressive-like behaviour (Dantzer et al. 2008) and, therefore, peripheral IL-1b could be a mediator of P2rx7 activation on mood-related changes.”

“The homo-oligomeric P2rx7 (Surprenant et al. 1996) has distinct structural, functional and pharmacological features within the P2X receptor family (Jarvis & Khakh, 2009 ; Sperlagh et al. 2006) : (1) its intracellular carboxyl-terminal domain is longer than those of other P2X receptor subunits ; (2)…”

“Automated tail suspension test (TST) This test was performed using an automated tail suspension device (BIO-TST2, Bioseb, France), following the method described in Cryan et al. (2005), which was connected to a computer that recorded the activity of the animals during test sessions.”

“A major immunomodulatory function of P2rx7 activation is that it acts as a necessary costimulus for the post-translational processing and subsequent release of the pro-inflammatory cytokine interleukin (IL)-1b in peripheral immune cells in response to bacterial endotoxin (Ferrari et al. 2006; Solle et al. 2001).”

“2001; Toro & Deakin, 2005), the antidepressant properties of glutamate receptor antagonists and modulators (Sanacora et al. 2008) and the regulation of glutamate receptor subunits by clinically used antidepressants (Nowak et al.”

“2006), P2rx7s might also act as a ‘danger signal’ and contribute to neurodegenerative and neuroplasticity events underlying a variety of central nervous system disorders from Alzheimer’s disease to mood disorders (Burnstock, 2008 ; Skaper et al. 2010; Sperlagh et al. 2006).”

“These include abnormalities in the level of glutamate (Hashimoto et al. 2007), genetic polymorphisms (Mundo et al. 2003), the differential expression of glutamate receptor subunits in bipolar and major depressive disorders (Meador-Woodruff et al. 2001; Toro & Deakin, 2005), the antidepressant…”

“The GeneCodis analysis generated a relationship of 373 annotation groups characterized with the Gene Ontology (GO) Biological Process, including transport, ion transport, signal transduction, synaptic transmission, G-protein coupled receptor protein signalling pathway, ATP synthesis coupled proton transport, transcrip…”

“These changes are consistent with previous results showing that the activation of P2rx7s in the brain leads to an increased glutamate and GABA release from nerve terminals (Papp et al. 2004; Patti et al. 2006; Sperlagh et al. 2002) and astrocytes (Duan et al. 2003).”

“Recent studies have shown that certain behavioural patterns, such as pathological grooming, can be transferred from one animal to another by immune cell transplantation (Chen et al. 2010).”

“The GeneCodis analysis generated a relationship of 373 annotation groups characterized with the Gene Ontology (GO) Biological Process, including transport, ion transport, signal transduction, synaptic transmission, G-protein coupled receptor protein signalling pathway, ATP synthesis coupled proton transport, transcrip…”

“BBG is a non-toxic and fairly selective antagonist of P2rx7s, which is able to penetrate the blood–brain barrier (Peng et al. 2009).”

“2006), P2rx7s might also act as a ‘danger signal’ and contribute to neurodegenerative and neuroplasticity events underlying a variety of central nervous system disorders from Alzheimer’s disease to mood disorders (Burnstock, 2008 ; Skaper et al. 2010; Sperlagh et al. 2006).”

“By regulating the activation and proliferation of microglia and the subsequent pathological process leading to neuronal death (Monif et al. 2009; Skaper et al. 2006), P2rx7s might also act as a ‘danger signal’ and contribute to neurodegenerative and neuroplasticity events underlying a variety of…”

“…disorders (Meador-Woodruff et al. 2001; Toro & Deakin, 2005), the antidepressant properties of glutamate receptor antagonists and modulators (Sanacora et al. 2008) and the regulation of glutamate receptor subunits by clinically used antidepressants (Nowak et al. 1998; Skolnick et al. 1996).”

“2006), P2rx7s might also act as a ‘danger signal’ and contribute to neurodegenerative and neuroplasticity events underlying a variety of central nervous system disorders from Alzheimer’s disease to mood disorders (Burnstock, 2008 ; Skaper et al. 2010; Sperlagh et al. 2006).”

“The homo-oligomeric P2rx7 (Surprenant et al. 1996) has distinct structural, functional and pharmacological features within the P2X receptor family (Jarvis & Khakh, 2009 ; Sperlagh et al. 2006) : (1) its intracellular carboxyl-terminal domain is longer than those of other P2X receptor subunits ; (2)…”

“2003), followed by increased glutamate and subsequent c-aminobutyric acid (GABA) release (Alloisio et al. 2008; Papp et al. 2004; Patti et al. 2006; Sperlagh et al. 2002).”

“The doses were chosen based on literature data (Diaz-Hernandez et al. 2009) and preliminary tests.”

“This treatment elicited the significant change of 570 transcripts with >2FC, which is comparable to the gene expression changes found by others in the brain after systemic endotoxin treatment (Marques et al. 2009; Marsh et al. 2009; Mastronardi et al. 2007; Perreau et al. 2007).”

“In line with previous data (Basso et al. 2009), P2rx7x/x mice spent significantly less time with immobility (i.”

“Accordingly, P2rx7s are involved in the regulation of different aspects of the hostdefence reaction (Chen & Brosnan, 2006 ; di Virgilio et al. 2009).”

“The primary role of P2rx7s in the brain is the modulation of neurotransmitter release (Anderson & Nedergaard, 2006; Sperlagh et al. 2006, 2007a).”

“2010) and are associated with bipolar disorder (Barden et al. 2006; Hejjas et al. 2009; McQuillin et al. 2009; Nagy et al. 2008; Soronen et al. 2011) and major depressive disorder (Lucae et al.”

“Microglia was prepared following the method described by Racz et al. (2008), with slight modifications.”

“2006) : (1) its intracellular carboxyl-terminal domain is longer than those of other P2X receptor subunits ; (2) it has several splice variants that display different functionality in P2rx7+/+ and knockout mice lines (Nicke et al. 2009) ; (3) its persistent activation elicits the opening of a membrane pore permeable to”

“…have revealed that non-synonymous single nucleotide polymorphisms in the human P2X7 gene (P2RX7) affect receptor function (Roger et al. 2010; Stokes et al. 2010) and are associated with bipolar disorder (Barden et al. 2006; Hejjas et al. 2009; McQuillin et al. 2009; Nagy et al. 2008;…”

“…et al. 2003), the differential expression of glutamate receptor subunits in bipolar and major depressive disorders (Meador-Woodruff et al. 2001; Toro & Deakin, 2005), the antidepressant properties of glutamate receptor antagonists and modulators (Sanacora et al. 2008) and the regulation of…”

“In accordance with the observations of Mayorga & Lucki (2001), a proportion of the animals (8.9% on average, 0–16%, depending on the experiment) displayed tail-climbing behaviour.”

“2011) and major depressive disorder (Lucae et al. 2006; Soronen et al. 2011; but see Green et al. 2009; Grigoroiu-Serbanescu et al. 2010; Lavebratt et al. 2010; Viikki et al. 2011).”

“2003), the differential expression of glutamate receptor subunits in bipolar and major depressive disorders (Meador-Woodruff et al. 2001; Toro & Deakin, 2005), the antidepressant properties of glutamate receptor antagonists and modulators (Sanacora et al.”

“Gene polymorphism studies have revealed that non-synonymous single nucleotide polymorphisms in the human P2X7 gene (P2RX7) affect receptor function (Roger et al. 2010; Stokes et al. 2010) and are associated with bipolar disorder (Barden et al. 2006; Hejjas et al. 2009; McQuillin et al. 2009; Nagy…”

“In contrast to rats, isolation does not increase but slightly decreases depressionlike behaviour in mice, at least in the Swiss strain of this species (Hilakivi et al. 1989).”

“Moreover, despite the emerging knowledge of the pathophysiology of mood disorders, a relatively high proportion of patients do not respond to existing medications (Martinowich et al. 2009; Sanacora et al. 2008), which urges the discovery and validation of new potential therapeutic targets.”

“Mice establish strong dominance hierarchies in both their natural habitats and the laboratory (Capanna et al. 1984; Ferrari et al. 1998; Poshivalov 1980).”

“This treatment elicited the significant change of 570 transcripts with >2FC, which is comparable to the gene expression changes found by others in the brain after systemic endotoxin treatment (Marques et al. 2009; Marsh et al. 2009; Mastronardi et al. 2007; Perreau et al. 2007).”

“1 allele as described previously (Jakus et al. 2009).”

“These observations confirm and extend previous data, which showed decreased immobility in the TST (Basso et al. 2009) and decreased floating time in the FST on the second day (Boucher et al. 2011) after genetic deletion.”

“These include abnormalities in the level of glutamate (Hashimoto et al. 2007), genetic polymorphisms (Mundo et al. 2003), the differential expression of glutamate receptor subunits in bipolar and major depressive disorders (Meador-Woodruff et al. 2001; Toro & Deakin, 2005), the antidepressant…”

“Systemic LPS administration (250 mg/ kg i.p.) caused a significant elevation in IL-1b levels (83.94¡3.01 pg/ml, n=8, F1,28=45.2, p 0.001, Fig.”

“The activation of P2rx7s elicits Ca2+ influx (Miras-Portugal et al. 2003), followed by increased glutamate and subsequent c-aminobutyric acid (GABA) release (Alloisio et al. 2008; Papp et al. 2004; Patti et al. 2006; Sperlagh et al. 2002).”

“2010) and are associated with bipolar disorder (Barden et al. 2006; Hejjas et al. 2009; McQuillin et al. 2009; Nagy et al. 2008; Soronen et al. 2011) and major depressive disorder (Lucae et al.”

“The activation of P2rx7s elicits Ca2+ influx (Miras-Portugal et al. 2003), followed by increased glutamate and subsequent c-aminobutyric acid (GABA) release (Alloisio et al. 2008; Papp et al. 2004; Patti et al. 2006; Sperlagh et al. 2002).”

“According to the current view, major depressive disorder and bipolar disorder are caused by plastic alterations of distributed networks involving multiple neurotransmitters and pathways (Stone et al. 2008).”

“Accordingly, P2rx7s are involved in the regulation of different aspects of the hostdefence reaction (Chen & Brosnan, 2006 ; di Virgilio et al. 2009).”

“As a behavioural model of manic pole of bipolar disorder (Einat, 2007), the AH test was used in our study.”

“…bipolar disorder (Barden et al. 2006; Hejjas et al. 2009; McQuillin et al. 2009; Nagy et al. 2008; Soronen et al. 2011) and major depressive disorder (Lucae et al. 2006; Soronen et al. 2011; but see Green et al. 2009; Grigoroiu-Serbanescu et al. 2010; Lavebratt et al. 2010; Viikki et al. 2011).”

“Our findings also indicated P2rx7-dependent changes in monoamine levels in the amygdala, which is an intrinsic part of the neuronal circuitry regulating emotions and the site of action of antidepressants (Castro et al. 2010).”

“…disorders (Meador-Woodruff et al. 2001; Toro & Deakin, 2005), the antidepressant properties of glutamate receptor antagonists and modulators (Sanacora et al. 2008) and the regulation of glutamate receptor subunits by clinically used antidepressants (Nowak et al. 1998; Skolnick et al. 1996).”

“2003), followed by increased glutamate and subsequent c-aminobutyric acid (GABA) release (Alloisio et al. 2008; Papp et al. 2004; Patti et al. 2006; Sperlagh et al. 2002).”

“The primary role of P2rx7s in the brain is the modulation of neurotransmitter release (Anderson & Nedergaard, 2006; Sperlagh et al. 2006, 2007a).”

“Biogenic amines were measured by a liquid–liquid, two-dimensional reversed phase and ion pair-reversed phase chromatographic separation, as described earlier (Baranyi et al. 2006) using a Gilson liquid chromatographic system (Gilson Medical Electronics Inc.”

“2010) and are associated with bipolar disorder (Barden et al. 2006; Hejjas et al. 2009; McQuillin et al. 2009; Nagy et al. 2008; Soronen et al. 2011) and major depressive disorder (Lucae et al.”

“The activation of P2rx7s elicits Ca2+ influx (Miras-Portugal et al. 2003), followed by increased glutamate and subsequent c-aminobutyric acid (GABA) release (Alloisio et al. 2008; Papp et al. 2004; Patti et al. 2006; Sperlagh et al. 2002).”

“Consistent with the presumed dysfunction of glutamatergic transmission and consequent neuroplasticity changes in depression (Sanacora, 2010 ; Sanacora et al. 2008), a downregulation of different a-amino-3-hydroxyl-5-methyl4-isoxazole-propionate (AMPA) and metabotropic glutamate receptor subunits…”

“Adrenocorticotropic hormone (ACTH) and corticosterone in the trunk blood and in acutely isolated pituitaries were measured by radioimmunoassay in 50-ml unextracted samples as described previously (Zelena et al. 2008).”

“2011) and major depressive disorder (Lucae et al. 2006; Soronen et al. 2011; but see Green et al. 2009; Grigoroiu-Serbanescu et al. 2010; Lavebratt et al. 2010; Viikki et al. 2011).”

“This treatment elicited the significant change of 570 transcripts with >2FC, which is comparable to the gene expression changes found by others in the brain after systemic endotoxin treatment (Marques et al. 2009; Marsh et al. 2009; Mastronardi et al. 2007; Perreau et al. 2007).”

“In contrast to rats, isolation does not increase but slightly decreases depressionlike behaviour in mice, at least in the Swiss strain of this species (Hilakivi et al. 1989).”

“Adrenocorticotropic hormone (ACTH) and corticosterone in the trunk blood and in acutely isolated pituitaries were measured by radioimmunoassay in 50-ml unextracted samples as described previously (Zelena et al. 2008).”

“These mutations might underlie the susceptibility to genetically related mood disorders (Harvey et al. 2007; Sluyter et al. 2010).”

“Mice establish strong dominance hierarchies in both their natural habitats and the laboratory (Capanna et al. 1984; Ferrari et al. 1998; Poshivalov 1980).”

“Functional P2rx7s are expressed on pituitary cells (Chung et al. 2000), which, together with our in vitro results, suggests a direct ATP effect on ACTH secretion.”

“This treatment elicited the significant change of 570 transcripts with >2FC, which is comparable to the gene expression changes found by others in the brain after systemic endotoxin treatment (Marques et al. 2009; Marsh et al. 2009; Mastronardi et al. 2007; Perreau et al. 2007).”

“[3H]Dopamine release experiments [3H]Dopamine release experiments on acute striatal slices were performed according to the method described in Milusheva et al. (2010).”

“These mutations might underlie the susceptibility to genetically related mood disorders (Harvey et al. 2007; Sluyter et al. 2010).”

“This finding is consistent with a report that a nonselective P2X7R antagonist decreases immobility in the FST only after repeated testing (59).”

“The beneficial effects of BBB-permeable P2X7 receptor antagonists in AD animal models also support the notion of pathological microglial activation in AD (Csölle et al., 2013).”

“[154] Gene Deletion”

“…in a model of sucrose consumption that is reflective of hedonic behavior, pharmacological antagonism of P2X7 (by AZ-10606120 and A-804598) restored the deficit observed in drinking sucrosewater (anhedonia) either under chronic stress or by systemic administration of LPS (Csolle et al., 2013b).”