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Increased surface P2X4 receptor regulates anxiety and memory in P2X4 internalization-defective knock-in mice

Abstract

ATP signaling and surface P2X4 receptors are upregulated selectively in neurons and/or glia in various CNS disorders including anxiety, chronic pain, epilepsy, ischemia, and neurodegenerative diseases. However, the cell-specific functions of P2X4 in pathological contexts remain elusive. To elucidate P2X4 functions, we created a conditional transgenic knock-in P2X4 mouse line (Floxed P2X4mCherryIN) allowing the Cre activity-dependent genetic swapping of the internalization motif of P2X4 by the fluorescent mCherry protein to prevent constitutive endocytosis of P2X4. By combining molecular, cellular, electrophysiological, and behavioral approaches, we characterized two distinct knock-in mouse lines expressing noninternalized P2X4mCherryIN either exclusively in excitatory forebrain neurons or in all cells natively expressing P2X4. The genetic substitution of wild-type P2X4 by noninternalized P2X4mCherryIN in both knock-in mouse models did not alter the sparse distribution and subcellular localization of P2X4 but increased the number of P2X4 receptors at the surface of the targeted cells mimicking the pathological increased surface P2X4 state. Increased surface P2X4 density in the hippocampus of knock-in mice altered LTP and LTD plasticity phenomena at CA1 synapses without affecting basal excitatory transmission. Moreover, these cellular events translated into anxiolytic effects and deficits in spatial memory. Our results show that increased surface density of neuronal P2X4 contributes to synaptic deficits and alterations in anxiety and memory functions consistent with the implication of P2X4 in neuropsychiatric and neurodegenerative disorders. Furthermore, these conditional P2X4mCherryIN knock-in mice will allow exploring the cell-specific roles of P2X4 in various physiological and pathological contexts.

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Fig. 1: Substitution of the internalization motif of P2X4 by mCherry increases ATP current density and surface expression of P2X4 receptors.
Fig. 2: Generation of conditional P2X4mCherryIN knock-in mice and P2X4 expression in CMV-Cre or CaMK2-Cre P2X4mCherryIN knock-in mice.
Fig. 3: Endogenous P2X4mCherryIN fluorescence in hippocampal microglia after LPS-induced de novo P2X4 expression and in peritoneal macrophages from CMV-P2X4mCherryIN mice.
Fig. 4: Surface P2X4mCherryIN expression is increased in hippocampal neurons of CaMK2 or CMV mice as well as in glial cells of CMV mice.
Fig. 5: Surface increase of neuronal P2X4 impairs LTP and LTD at CA1 hippocampal synapses and alters anxiety, spatial learning, and memory.

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Acknowledgements

We thank G. Dabee for the production of all transgenic mice at the animal facility, H. Orignac for help with Xenopus facilities and E. Normand for stereotaxic injection. We thank the Mouse Clinical Institute (Institut Clinique de la Souris, MCI/ICS) in the Genetic Engineering and Model Validation Department who established the mouse mutant floxed P2X4mCherryIN line. We are grateful to F. Rassendren (IGF, Montpellier) for providing P2X4KO mice. We also thank the biochemistry facility of Bordeaux Neurocampus. Electron microscopy was performed at the Bordeaux Imaging Center, a service unit of the CNRS-INSERM and Bordeaux University. This work was supported by CNRS, University of Bordeaux, a grant LabEx BRAIN ANR-10-LABX-43 to EB-G and EB, a grant from Inserm for the generation of the mouse line to EB-G, the Louise and Alan Edwards Foundation, an awarded grant from Quebec Pain Research Network (QPRN) to TD, International Ph. D program of the IdEx of Bordeaux to EB-G and PS and DFG grant SFB1328-Z02 to FK-N.

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EB, TD, KSP, AM, J-TP, ED, A-EA, ET, MR, FG, ON performed the experiments and analyzed the data. PS, BB, SL, FG, SB, ON and EB-G designed the experiments and analyzed the data. PB, EB, FK-N contributed with key reagents. EB-G conceived the knock-in mice and the study. KSP, ON, and EB-G wrote the paper. All authors commented the paper.

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Correspondence to Eric Boué-Grabot.

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Bertin, E., Deluc, T., Pilch, K.S. et al. Increased surface P2X4 receptor regulates anxiety and memory in P2X4 internalization-defective knock-in mice. Mol Psychiatry 26, 629–644 (2021). https://doi.org/10.1038/s41380-019-0641-8

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