P2X7 Receptor-Dependent Layer-Specific Changes in Neuron-Microglia Reactivity in the Prefrontal Cortex of a Phencyclidine Induced Mouse Model of Schizophrenia.
P2X7 Receptor-Dependent Layer-Specific Changes in Neuron-Microglia Reactivity in the Prefrontal Cortex of a Phencyclidine Induced Mouse Model of Schizophrenia.
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DOI：
10.3389/fnmol.2020.566251
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发表时间：
2020
影响因子：
4.8
通讯作者：
Sperlagh B
中科院分区：
文献类型：
--
作者：
Calovi S;Mut-Arbona P;Tod P;Iring A;Nicke A;Mato S;Vizi ES;Tønnesen J;Sperlagh B
背景资料：一直有报道称，三磷酸腺苷（ATP）敏感性嘌呤能受体P2 X7（P2 X7 R）的缺乏可改善脑疾病动物模型中的症状。目的：本研究旨在研究P2 X7 R在急性和亚慢性精神分裂症的啮齿动物模型的基础上，苯环己哌啶（PCP）交付的动物缺乏或过表达P2 X7 R的作用，并确定相关的机制。研究方法：对C57 Bl/6 J野生型、P2 X7 R敲除（P2 rx 7 −/−）和过表达（P2 X7-EGFP）的年轻成年小鼠急性腹腔注射PCP的拟精神病效应进行了定量。通过免疫组织化学染色表征P2 rx 7 −/−和杂合P2 X7-EGFP急性处理的动物的内侧前额叶皮质（mPFC）。年轻成年P2 rx 7 −/−和P2 rx 7 tg/+小鼠的前额叶皮质通过氚标记多巴胺释放实验进行了检查，P2 rx 7 −/−小鼠V层mPFC锥体神经元的功能特性通过膜片钳记录进行了评估。对P2 rx 7 −/−动物进行7天亚慢性全身PCP处理。评估动物的工作记忆表现和PFC细胞因子水平。结果如下：我们的数据加强了这样的假设，即P2 X7 R调节精神分裂症样的积极和认知症状的NMDA受体拮抗剂模型中的受体表达水平依赖性的方式。P2 X7 R表达导致内侧PFC对PCP诱导的回路过度活跃的易感性更高。P2 X7 R基因敲除动物的mPFC在神经元激活模式、小胶质细胞组织（特别是在过度活跃的神经元周围）方面显示出明显的改变，并且与mPFC神经元的内在兴奋性降低相关。结论：P2 X7 R表达加重了C57 Bl/6 J小鼠PCP相关效应。我们的研究结果表明P2 X7 R在mPFC中的多效性作用，与观察到的行为表型一致，调节基础多巴胺浓度，层特异性神经元激活，mPFC中神经元的内在兴奋性，以及小胶质细胞与过度活跃神经元的相互作用。直接测量P2 X7 R活性有关的小胶质细胞分支和动力学可能有助于进一步阐明所涉及的分子机制。
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.
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影响因子：
2.9
作者：
Day, Heidi E. W.;Kryskow, Elisa M.;Nyhuis, Tara J.;Herlihy, Lauren;Campeau, Serge
通讯作者：
Campeau, Serge
影响因子：
7.3
作者：
Bhattacharya, Anindya;Wang, Qi;Letavic, Michael A.
通讯作者：
Letavic, Michael A.
影响因子：
4
作者：
Diaz-Hernandez, Miguel;del Puerto, Ana;Miras-Portugal, Maria Teresa
通讯作者：
Miras-Portugal, Maria Teresa
影响因子：
5.6
作者：
Bhattacharya A
通讯作者：
Bhattacharya A
影响因子：
8.8
作者：
Eyo UB;Mo M;Yi MH;Murugan M;Liu J;Yarlagadda R;Margolis DJ;Xu P;Wu LJ
通讯作者：
Wu LJ