Suppression of Presynaptic Glutamate Release by Postsynaptic Metabotropic NMDA Receptor Signalling to Pannexin-1.

Jennifer Bialecki, Allison Werner, Nicholas L Weilinger, Catharine M Tucker, Haley A Vecchiarelli, Jon Egaña, Juan Mendizabal-Zubiaga, Pedro Grandes, Matthew N Hill, Roger J Thompson

The Journal of neuroscience : the official journal of the Society for Neuroscience 2020 Jan 22

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The impact of pannexin-1 (Panx1) channels on synaptic transmission is poorly understood. Here, we show that selective block of Panx1 in single postsynaptic hippocampal CA1 neurons from male rat or mouse brain slices causes intermittent, seconds long increases in the frequency of sEPSC following Schaffer collateral stimulation. The increase in sEPSC frequency occurred without an effect on evoked neurotransmission. Consistent with a presynaptic origin of the augmented glutamate release, the increased sEPSC frequency was prevented by bath-applied EGTA-AM or TTX. Manipulation of a previously described metabotropic NMDAR pathway (i.e., by preventing ligand binding to NMDARs with competitive antagonists or blocking downstream Src kinase) also increased sEPSC frequency similar to that seen when Panx1 was blocked. This facilitated glutamate release was absent in transient receptor potential vanilloid 1 (TRPV1) KO mice and prevented by the TRPV1 antagonist, capsazepine, suggesting it required presynaptic TRPV1. We show presynaptic expression of TRPV1 by immunoelectron microscopy and link TRPV1 to Panx1 because Panx1 block increases tissue levels of the endovanilloid, anandamide. Together, these findings demonstrate an unexpected role for metabotropic NMDARs and postsynaptic Panx1 in suppression of facilitated glutamate neurotransmission.SIGNIFICANCE STATEMENT The postsynaptic ion and metabolite channel, pannexin-1, is regulated by metabotropic NMDAR signaling through Src kinase. This pathway suppresses facilitated release of presynaptic glutamate during synaptic activity by regulating tissue levels of the transient receptor potential vanilloid 1 agonist anandamide. Copyright © 2020 the authors.

Citation

Jennifer Bialecki, Allison Werner, Nicholas L Weilinger, Catharine M Tucker, Haley A Vecchiarelli, Jon Egaña, Juan Mendizabal-Zubiaga, Pedro Grandes, Matthew N Hill, Roger J Thompson. Suppression of Presynaptic Glutamate Release by Postsynaptic Metabotropic NMDA Receptor Signalling to Pannexin-1. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2020 Jan 22;40(4):729-742