Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, 1083, Budapest, Hungary.
János Szentágothai Doctoral School, Semmelweis University, 1085, Budapest, Hungary.
J Neurosci. 2023 Feb 15;43(7):1125-1142. doi: 10.1523/JNEUROSCI.0805-22.2022. Epub 2023 Feb 2.
At high levels, extracellular ATP operates as a "danger" molecule under pathologic conditions through purinergic receptors, including the ionotropic P2X7 receptor (P2X7R). Its endogenous activation is associated with neurodevelopmental disorders; however, its function during early embryonic stages remains largely unclear. Our objective was to determine the role of P2X7R in the regulation of neuronal outgrowth. For this purpose, we performed Sholl analysis of dendritic branches on primary hippocampal neurons and in acute hippocampal slices from WT mice and mice with genetic deficiency or pharmacological blockade of P2X7R. Because abnormal dendritic branching is a hallmark of certain neurodevelopmental disorders, such as schizophrenia, a model of maternal immune activation (MIA)-induced schizophrenia, was used for further morphologic investigations. Subsequently, we studied MIA-induced behavioral deficits in young adult mice females and males. Genetic deficiency or pharmacological blockade of P2X7R led to branching deficits under physiological conditions. Moreover, pathologic activation of the receptor led to deficits in dendritic outgrowth on primary neurons from WT mice but not those from P2X7R KO mice exposed to MIA. Likewise, only MIA-exposed WT mice displayed schizophrenia-like behavioral and cognitive deficits. Therefore, we conclude that P2X7R has different roles in the development of hippocampal dendritic arborization under physiological and pathologic conditions. Our main finding is a novel role for P2X7R in neuronal branching in the early stages of development under physiological conditions. We show how a decrease in the expression of P2X7R during brain development causes the receptor to play pathologic roles in adulthood. Moreover, we studied a neurodevelopmental model of schizophrenia and found that, at higher ATP concentrations, endogenous activation of P2X7R is necessary and sufficient for the development of positive and cognitive symptoms.
在病理条件下，细胞外 ATP 作为一种“危险”分子通过嘌呤能受体（包括离子型 P2X7 受体（P2X7R））发挥作用。其内源性激活与神经发育障碍有关；然而，其在早期胚胎阶段的功能在很大程度上仍不清楚。我们的目的是确定 P2X7R 在神经元生长调节中的作用。为此，我们对 WT 小鼠和 P2X7R 基因缺失或药理学阻断的急性海马切片中的原代海马神经元的树突分支进行了 Sholl 分析。由于异常的树突分支是某些神经发育障碍的标志，如精神分裂症，因此使用了母体免疫激活（MIA）诱导的精神分裂症模型进行进一步的形态学研究。随后，我们研究了年轻成年雌性和雄性小鼠的 MIA 诱导的行为缺陷。在生理条件下，P2X7R 的基因缺失或药理学阻断导致分支缺陷。此外，病理性激活受体导致 WT 小鼠而非暴露于 MIA 的 P2X7R KO 小鼠的原代神经元的树突生长缺陷。同样，只有暴露于 MIA 的 WT 小鼠表现出类似精神分裂症的行为和认知缺陷。因此，我们得出结论，P2X7R 在生理和病理条件下对海马树突分支的发育有不同的作用。我们的主要发现是 P2X7R 在生理条件下早期发育中神经元分支的新作用。我们展示了在大脑发育过程中 P2X7R 表达减少如何导致受体在成年期发挥病理性作用。此外，我们研究了精神分裂症的神经发育模型，发现内源性激活 P2X7R 在较高 ATP 浓度下是发展阳性和认知症状所必需和充分的。
