Increased surface P2X4 receptor regulates anxiety and memory in P2X4 internalization-defective knock-in mice
Mol Psychiatry. 2020-01-08; :
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Bertin E(1)(2), Deluc T(1)(2)(3), Pilch KS(1)(2), Martinez A(1)(2), Pougnet JT(1)(2), Doudnikoff E(1)(2), Allain AE(4)(5), Bergmann P(6), Russeau M(7), Toulmé E(1)(2), Bezard E(1)(2), Koch-Nolte F(6), Séguéla P(3), Lévi S(7), Bontempi B(1)(2), Georges F(1)(2), Bertrand SS(4)(5), Nicole O(1)(2), Boué-Grabot E(8)(9).
(1)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000, Bordeaux, France.
(2)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000, Bordeaux, France.
(3)Department of Neurology and Neurosurgery, Montreal Neurological Institute, Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A2B4, Canada.
(4)Université de Bordeaux, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, UMR5287, F-33000, Bordeaux, France.
(5)CNRS, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, UMR5287, F-33000, Bordeaux, France.
(6)Institute of Immunology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany.
(7)INSERM UMR-S 1270, Sorbonne Université, Institut du Fer à Moulin, 75005, Paris, France.
(8)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000, Bordeaux, France. .
(9)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000, Bordeaux, France. .
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.