Abstract
Background: It has been consistently reported that the deficiency of the adenosine triphosphate (ATP) sensitive purinergic receptor P2X7 (P2X7R) ameliorates symptoms in animal models of brain diseases.Objective: This study aimed to investigate the role of P2X7R in rodent models of acute and subchronic schizophrenia based on phencyclidine (PCP) delivery in animals lacking or overexpressing P2X7R, and to identify the underlying mechanisms involved.Methods: The psychotomimetic effects of acute i.p. PCP administration in C57Bl/6J wild-type, P2X7R knockout (P2rx7−/−) and overexpressing (P2X7-EGFP) young adult mice were quantified. The medial prefrontal cortex (mPFC) of P2rx7−/− and heterozygous P2X7-EGFP acutely treated animals was characterized through immunohistochemical staining. The prefrontal cortices of young adult P2rx7−/− and P2rx7tg/+ mice were examined with tritiated dopamine release experiments and the functional properties of the mPFC pyramidal neurons in layer V from P2rx7−/− mice were assessed by patch-clamp recordings. P2rx7−/− animals were subjected to a 7 days subchronic systemic PCP treatment. The animals working memory performance and PFC cytokine levels were assessed.Results: Our data strengthen the hypothesis that P2X7R modulates schizophrenia-like positive and cognitive symptoms in NMDA receptor antagonist models in a receptor expression level-dependent manner. P2X7R expression leads to higher medial PFC susceptibility to PCP-induced circuit hyperactivity. The mPFC of P2X7R knockout animals displayed distinct alterations in the neuronal activation pattern, microglial organization, specifically around hyperactive neurons, and were associated with lower intrinsic excitability of mPFC neurons.Conclusions: P2X7R expression exacerbated PCP-related effects in C57Bl/6J mice. Our findings suggest a pleiotropic role of P2X7R in the mPFC, consistent with the observed behavioral phenotype, regulating basal dopamine concentration, layer-specific neuronal activation, intrinsic excitability of neurons in the mPFC, and the interaction of microglia with hyperactive neurons. Direct measurements of P2X7R activity concerning microglial ramifications and dynamics could help to further elucidate the molecular mechanisms involved.
Highlights
Schizophrenia (SCZ), which has a prevalence of 0.7% in adults, is a severe psychiatric disorder characterized by abnormalities in thought and cognition (Powchik et al, 1998)
The Real-time quantitative PCR (RT-qPCR) measurement revealed that the disrupted sequence in P2rx7−/− mice was markedly reduced compared to the P2rx7+/+ mice, while no difference was detected regarding the extra- and intracellular sequences between the knockout and WT mice (Figure 1C)
The visualization of room temperature (RT)-qPCR products by electrophoretic separation confirmed that the band (90 bp), corresponding to the disrupted sequence in P2rx7−/− mice, appeared only in the P2rx7+/+, while the bands corresponding to the extra, and intracellular regions of P2X7 receptor were detected in both the WT and in the KO mice
Summary
Schizophrenia (SCZ), which has a prevalence of 0.7% in adults, is a severe psychiatric disorder characterized by abnormalities in thought and cognition (Powchik et al, 1998). The pathology of SCZ is typically recognized by multiple psychotic episodes, along with a progressive worsening of social and cognitive abilities and multifactorial tissue deterioration of key brain areas, such as the prefrontal cortex (PFC; Lesh et al, 2011). While it is known that P2X7R is expressed in the brain, the exact cell-type specific localization of the receptors has been the subject of extensive debate (Illes et al, 2017; Teresa Miras-Portugal et al, 2017). Novel findings using the enhanced green fluorescent protein P2X7-EGFP reporter mouse line, which overexpresses the EGFP C-terminally tagged receptor protein, indicates that P2X7R, at least in the mouse brain, is preferentially expressed by microglia and oligodendroglial cells (Kaczmarek-Hajek et al, 2018). It has been consistently reported that the deficiency of the adenosine triphosphate (ATP) sensitive purinergic receptor P2X7 (P2X7R) ameliorates symptoms in animal models of brain diseases
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