Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors

Abstract

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7−/−) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7−/− mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7−/− mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7−/− mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7−/− mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7−/− mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7−/− mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7−/− mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus.

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

“…This correlates with the positive outcomes reported in two different Alzheimer's disease models that used P2X7 antagonists (Ryu and McLarnon, 2008;Diaz-Hernandez et al, 2012). Second, in models of depression, P2X7 KO mice displayed antidepressant-like profiles in comparison with WT controls (Basso et al, 2009;Boucher et al, 2011;Csölle et al, 2013). Two different P2X7 antagonists (BBG and AZ10606120) also induced an antidepressant phenotype in WT mice (Csölle et al, 2013).…”

“…Second, in models of depression, P2X7 KO mice displayed antidepressant-like profiles in comparison with WT controls (Basso et al, 2009;Boucher et al, 2011;Csölle et al, 2013). Two different P2X7 antagonists (BBG and AZ10606120) also induced an antidepressant phenotype in WT mice (Csölle et al, 2013). However, the antagonist JNJ-47965567 had no effect on models of depression, although this antagonist was P2X7 Antagonists in Models of Disease Kim et al, 2011 (continued ) 654 efficacious and slightly effective, respectively, in models of mania and neuropathic pain (Bhattacharya et al, 2013).…”

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…Acute stress induced depressiveelike behaviors, following LPS challenge are also alleviated by P2X7 receptor antagonism, (Csolle et al, 2013b;Ma et al, 2014). When footshocks were used as a stressor, however, no change in behavior was found in the presence of a P2X7 antagonist (Catanzaro et al, 2014).…”

“…However, it appears that the scenario is more complex as only LPS-induced, but not the basal IL-1b levels are subject to regulation by P2X7 receptors in the rodent brain (Csolle and Sperlagh, 2010;Mingam et al, 2008) and the mood stabilizing phenotype detected in the absence of P2X7 receptors was not transferred with bone marrow transplantation (Csolle et al, 2013b). The contribution of P2X7 receptors present on cells of hematopoietic origin such as peripheral immune cells to behavioral changes detected in naïve animals, therefore, seems minimal.…”

“…Rather, P2X7-regulated intrinsic neuronal mechanisms such as the modulation of glutamatergic neurotransmission (Csolle et al, 2013b) or nitric oxide signaling (Pereira et al, 2013) may represent the underlying mechanisms of the antidepressant phenotype. On the other hand, amphetamine induced induction of IL-1b and oxidative stress (Gubert et al, 2014) in the striatum were reversed by a P2X7 receptor antagonist coincidently with the alleviation of amphetamine induced behavior and amphetamine induced striatal dopamine release is attenuated by the P2X7 receptor deficient genotype (Csolle et al, 2013a).…”