The regulatory effect of purinergic P2X7Rs on the excitatory neurotransmission and the mouse model of schizophrenia
Lumei Huang
János Szentágothai Neurosciences
Dr. Bereczki Dániel
MTA KOKI előadóterem
2024-04-30 10:00:00
Functional neurosciences
Dr. Sperlágh Beáta
Dr. Sperlágh Beáta
Dr. Czirják Gábor
Dr. Veres Judit
Dr. Köles László
Dr. Al-Khrasani Mahmoud
Dr. Némethy Zsolt
ATP-gated P2X7Rs play a crucial role in brain disorders, mainly by regulating glial cell activity. However, their neuronal mechanisms remain controversial and unclear. Therefore, we investigated the involvement of P2X7Rs in excitatory neurotransmission in dentate gyrus granule cells (DG-GCs) of the hippocampus and in a postnatal phencyclidine (PCP)-induced schizophrenia mouse model.
To address these questions, we first recorded AMPA and NMDA-receptor-mediated spontaneous excitatory postsynaptic currents (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) in both WT and P2X7R-deficient mice utilizing the in vitro whole-cell patch-clamp technique. We found that genetic ablation of P2X7Rs decreased the frequency, but not the amplitude, of AMPA and NMDA receptor-mediated EPSCs. The direct involvement of P2X7Rs was confirmed by a pharmacological approach. Paired pulse ratio (PPR) analysis further indicated that the entorhinal cortex (EC)-GC pathway (perforant path), but not the mossy cell (MC)-GC pathway, was associated with DG neurotransmitter regulation mediated by P2X7Rs. To further understand the intracellular mechanism of the EC GC pathway, we injected pAAV1-hSynapsin1-axon-GaMP6s into EC and measured the Ca2+ influx of the EC GC pathway with a multiphoton microscopy. Ca2+ imaging showed that activation of P2X7Rs directly increased the Ca2+ influx into EC-GC boutons. To validate the role of P2X7R in pathological states, we established a neurodevelopment model of schizophrenia by postnatal PCP injection and tested the behaviour changes in juveniles and young adults. We observed that P2X7Rs deletion restored the AMPA/NMDA ratio at EC-GC synapses and attenuated PCP-induced schizophrenia-like behaviours. We also established a rat model of CFA-induced inflammatory pain and found that pharmacological inhibition of P2X7Rs significantly relieved CFA-induced acute thermal pain sensation.
Taken together, P2X7Rs are involved in the modulation of excitatory neurotransmission onto the DG GC through the EC-GC pathway by directly increasing the Ca2+ influx. In addition, P2X7Rs may be potential therapeutic targets for the treatment of schizophrenia and pain.
