Huang Lumei, Mut-Arbona Paula, Varga Bernadett, Török Bibiana, Brunner János, Arszovszki Antonia, Iring András, Kisfali Máté, Vizi E Sylvester, Sperlágh Beáta
Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, 1083 Budapest, Hungary.
János Szentágothai Doctoral School, Semmelweis University, 1085 Budapest, Hungary.
iScience. 2023 Aug 7;26(9):107560. doi: 10.1016/j.isci.2023.107560. eCollection 2023 Sep 15.
ATP-gated P2X7 receptors (P2X7Rs) play a crucial role in brain disorders. However, how they affect normal and pathological synaptic transmission is still largely unclear. Here, by using whole-cell patch-clamp technique to record AMPA- and NMDA receptor-mediated excitatory postsynaptic currents (s/mEPSCs) in dentate gyrus granule cells (DG GCs), we revealed a modulation by P2X7Rs of presynaptic sites, especially originated from entorhinal cortex (EC)-GC path but not the mossy cell (MC)-GC path. The involvement of P2X7Rs was confirmed using a pharmacological approach. Additionally, the acute activation of P2X7Rs directly elevated calcium influx from EC-GC terminals. In postnatal phencyclidine (PCP)-induced mouse model of schizophrenia, we observed that P2X7R deficiency restored the EC-GC synapse alteration and alleviated PCP-induced symptoms. To summarize, P2X7Rs participate in the modulation of GC excitatory neurotransmission in the DG via EC-GC pathway, contributing to pathological alterations of neuronal functions leading to neurodevelopmental disorders.
三磷酸腺苷（ATP）门控的P2X7受体（P2X7Rs）在脑部疾病中起关键作用。然而，它们如何影响正常和病理性突触传递在很大程度上仍不清楚。在此，我们通过使用全细胞膜片钳技术记录齿状回颗粒细胞（DG GCs）中α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和N-甲基-D-天冬氨酸（NMDA）受体介导的兴奋性突触后电流（s/mEPSCs），揭示了P2X7Rs对突触前位点的调节作用，尤其是起源于内嗅皮质（EC）-GC通路而非苔藓细胞（MC）-GC通路的调节作用。使用药理学方法证实了P2X7Rs的参与。此外，P2X7Rs的急性激活直接增加了来自EC-GC终末的钙内流。在出生后苯环利定（PCP）诱导的精神分裂症小鼠模型中，我们观察到P2X7R缺陷恢复了EC-GC突触改变并减轻了PCP诱导的症状。总之，P2X7Rs通过EC-GC通路参与DG中GC兴奋性神经传递的调节，导致神经元功能的病理性改变，进而引发神经发育障碍。
