Increased surface P2X4 receptor regulates anxiety and memory in P2X4 internalization-defective knock-in mice
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Increased surface P2X4 receptor regulates anxiety and memory in P2X4 internalization-defective knock-in mice. / Bertin, Eléonore; Deluc, Thomas; Pilch, Kjara S; Martinez, Audrey; Pougnet, Johan-Till; Doudnikoff, Evelyne; Allain, Anne-Emilie; Bergmann, Philine; Russeau, Marion; Toulmé, Estelle; Bezard, Erwan; Koch-Nolte, Friedrich; Séguéla, Philippe; Lévi, Sabine; Bontempi, Bruno; Georges, François; Bertrand, Sandrine S; Nicole, Olivier; Boué-Grabot, Eric.
In: MOL PSYCHIATR, Vol. 26, No. 2, 02.2021, p. 629-644.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Increased surface P2X4 receptor regulates anxiety and memory in P2X4 internalization-defective knock-in mice
AU - Bertin, Eléonore
AU - Deluc, Thomas
AU - Pilch, Kjara S
AU - Martinez, Audrey
AU - Pougnet, Johan-Till
AU - Doudnikoff, Evelyne
AU - Allain, Anne-Emilie
AU - Bergmann, Philine
AU - Russeau, Marion
AU - Toulmé, Estelle
AU - Bezard, Erwan
AU - Koch-Nolte, Friedrich
AU - Séguéla, Philippe
AU - Lévi, Sabine
AU - Bontempi, Bruno
AU - Georges, François
AU - Bertrand, Sandrine S
AU - Nicole, Olivier
AU - Boué-Grabot, Eric
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
U2 - 10.1038/s41380-019-0641-8
DO - 10.1038/s41380-019-0641-8
M3 - SCORING: Journal article
C2 - 31911635
VL - 26
SP - 629
EP - 644
JO - MOL PSYCHIATR
JF - MOL PSYCHIATR
SN - 1359-4184
IS - 2
ER -