P2X7 purinergic receptor modulates dentate gyrus excitatory neurotransmission and alleviates schizophrenia-like symptoms in mouse

Lumei Huang; Paula Mut-Arbona; Bernadett Varga; Bibiana Török; János Brunner; Antonia Arszovszki; András Iring; Máté Kisfali; E Sylvester Vizi; Beáta Sperlágh

doi:10.1016/j.isci.2023.107560

P2X7 purinergic receptor modulates dentate gyrus excitatory neurotransmission and alleviates schizophrenia-like symptoms in mouse

iScience. 2023 Aug 7;26(9):107560. doi: 10.1016/j.isci.2023.107560. eCollection 2023 Sep 15.

Authors

Lumei Huang^{1

2}, Paula Mut-Arbona^{1

2}, Bernadett Varga^{1

2}, Bibiana Török¹, János Brunner³, Antonia Arszovszki³, András Iring¹, Máté Kisfali⁴, E Sylvester Vizi^{1

2}, Beáta Sperlágh^{1

2}

Affiliations

¹ Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, 1083 Budapest, Hungary.
² János Szentágothai Doctoral School, Semmelweis University, 1085 Budapest, Hungary.
³ Laboratory of Cellular Neuropharmacology, Institute of Experimental Medicine, 1083 Budapest, Hungary.
⁴ Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, 1083 Budapest, Hungary.

Abstract

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.

Keywords: Behavioral neuroscience; Biological sciences; Natural sciences; Neuroscience; Pharmacology; Physiology.