The role of P2X7 receptors in a rodent PCP-induced schizophrenia model

Abstract

P2X7 receptors (P2X7Rs) are ligand-gated ion channels sensitive to extracellular ATP. Here we examined for the first time the role of P2X7R in an animal model of schizophrenia. Using the PCP induced schizophrenia model we show that both genetic deletion and pharmacological inhibition of P2X7Rs alleviate schizophrenia-like behavioral alterations. In P2rx7+/+ mice, PCP induced hyperlocomotion, stereotype behavior, ataxia and social withdrawal. In P2X7 receptor deficient mice (P2rx7−/−), the social interactions were increased, whereas the PCP induced hyperlocomotion and stereotype behavior were alleviated. The selective P2X7 receptor antagonist JNJ-47965567 partly replicated the effect of gene deficiency on PCP-induced behavioral changes and counteracted PCP-induced social withdrawal. We also show that PCP treatment upregulates and increases the functional responsiveness of P2X7Rs in the prefrontal cortex of young adult animals. The amplitude of NMDA evoked currents recorded from layer V pyramidal neurons of cortical slices were slightly decreased by both genetic deletion of P2rx7 and by JNJ-47965567. PCP induced alterations in mRNA expression encoding schizophrenia-related genes, such as NR2A, NR2B, neuregulin 1, NR1 and GABA α1 subunit were absent in the PFC of young adult P2rx7−/− animals. Our findings point to P2X7R as a potential therapeutic target in schizophrenia.

P2X7 receptors drive poly(I:C) induced autism-like behavior in mice

“…11). P2rx7s and downstream signaling pathways coupled to them are common signaling highways in the pathological nervous system; their involvement has been shown previously in animal models of psychiatric disorders (Cheffer et al, 2018), such as major depression, bipolar disorder (Basso et al, 2009;Csölle et al, 2013a, b), schizophrenia (Koványi et al, 2016), but not in ASD models. The experimental proof for endogenous P2rx7s participation in MIA-induced behavioral and morphological changes in the offspring are as follows: (1) In P2rx7 Ϫ/Ϫ mice, maternal poly(I:C) did not induce social deficit, sensorimotor impairment, repetitive behaviors; in addition, cerebellar Purkinje cell atrophy and synaptosome destruction were also absent or alleviated.…”

“…Experiments were performed on male and female P2rx7 ϩ/ϩ (C57BL/6) and P2rx7-deficient mice (weighing 25-30 g) for breeding, and their male offspring for behavior and further experiments. P2rx7 Ϫ/Ϫ mice were obtained, bred, and genotyped as described previously (Koványi et al, 2016). Briefly, homozygous P2rx7 ϩ/ϩ mice were bred on a C57BL/6J background.…”

Regulation of Hippocampal 5-HT Release by P2X7 Receptors in Response to Optogenetic Stimulation of Median Raphe Terminals of Mice

“…Our data showing the P2rx7 -mediated modulation of [ 3 H]5-HT release are not contradictory with previous findings reporting elevation in endogenous 5-HT level and inhibition of 5-HT transporters in case of genetic deletion and the pharmacological blockade of P2rx7 s ( Csolle et al, 2013b ; Lord et al, 2014 ). These changes might be independent and compensatory changes as well, pointing to the complex regulation of serotonergic transmission by P2rx7 s. The regulation of 5-HT efflux by P2rx7s might also gain significance in psychiatric disorders as recent studies pointed out the alleviation of depression- and schizophrenia-like behaviors in rodent animal models by the inhibition of P2rx7s ( Csolle et al, 2013a , b ; Kovanyi et al, 2016 ).…”

“…The activation of P2rx7 s elicit glutamate and subsequent GABA release from the HP ( Sperlagh et al, 2002 ), but also mediates the release of the endogenous P2rx7 agonist ATP ( Heinrich et al, 2012 ). P2rx7 s have been shown to contribute to the pathophysiology of depression ( Csolle et al, 2013a , b ; Iwata et al, 2016 ; Otrokocsi et al, 2017 ), bipolar disorder ( Csolle et al, 2013a ; Lord et al, 2014 ) and schizophrenia ( Kovanyi et al, 2016 ). However, the regulation of serotonergic transmission by P2rx7 s have been remained controversial so far.…”

Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia

“…In addition to depression, preclinical data also suggest that P2X7 antagonism may produce anti-manic or mood stabilizing effects in bipolar disorder [34]. More recently, the role of P2X7 in the PCP model of schizophrenia has come to light [35]. The current body of data suggests that a selective and brain-penetrant P2X7 antagonist may be therapeutically beneficial in several neuropsychiatric disorders [36].…”