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 P2rx7^tg/+ 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.

背景：一直以来都有报道说，三磷酸腺苷（ATP）敏感的嘌呤能受体P2X7（P2X7R）的缺乏改善了脑疾病动物模型中的症状。

目的：这项研究旨在调查在缺乏或过度表达P2X7R的动物中，基于苯环利定（PCP）递送的P2X7R在急性和亚慢性精神分裂症啮齿动物模型中的作用，并确定其潜在的机制。

方法：定量了急性ip PCP给药对C57Bl / 6J野生型，P2X7R敲除（P2rx7 ^-/-）和过表达（P2X7-EGFP）幼年成年小鼠的拟精神效应。通过免疫组织化学染色对P2rx7 ^-/-和杂合P2X7-EGFP急性处理的动物的内侧前额叶皮层（mPFC）进行了表征。用tri化的多巴胺释放实验检查了成年P2rx7 ^-/-和P2rx7 ^{tg / +}小鼠的前额叶皮层，并通过膜片钳记录评估了P2rx7 ^-/-小鼠V层中mPFC锥体神经元的功能特性。P2rx7 ^-/-对动物进行7天的亚慢性全身PCP治疗。评估动物的工作记忆性能和PFC细胞因子水平。

结果：我们的数据证实了P2X7R以受体表达水平依赖性方式调节NMDA受体拮抗剂模型中精神分裂症样阳性和认知症状的假设。P2X7R表达导致PCP诱导的电路亢进性较高的内侧PFC敏感性。P2X7R基因敲除动物的mPFC在神经元激活模式，小神经胶质组织（特别是在过度活跃的神经元周围）表现出明显的变化，并且与mPFC神经元的较低固有兴奋性相关。

结论：P2X7R表达在C57Bl / 6J小鼠中加剧了PCP相关的作用。我们的发现表明P2X7R在mPFC中具有多效作用，与观察到的行为表型，调节基础多巴胺浓度，层特异性神经元活化，mPFC中神经元的固有兴奋性以及小胶质细胞与过度活跃神经元的相互作用相一致。有关小胶质细胞分支和动力学的P2X7R活性的直接测量可以帮助进一步阐明所涉及的分子机制。