title: Prion protein is a key determinant of alcohol sensitivity through the modulation of N-methyl-D-aspartate receptor (NMDAR) activity.
abstract: The prion protein (PrP) is absolutely required for the development of prion diseases; nevertheless, its physiological functions in the central nervous system remain elusive. Using a combination of behavioral, electrophysiological and biochemical approaches in transgenic mouse models, we provide strong evidence for a crucial role of PrP in alcohol sensitivity. Indeed, PrP knock out (PrP(-/-)) mice presented a greater sensitivity to the sedative effects of EtOH compared to wild-type (wt) control mice. Conversely, compared to wt mice, those over-expressing mouse, human or hamster PrP genes presented a relative insensitivity to ethanol-induced sedation. An acute tolerance (i.e. reversion) to ethanol inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potentials in hippocampal slices developed slower in PrP(-/-) mice than in wt mice. We show that PrP is required to induce acute tolerance to ethanol by activating a Src-protein tyrosine kinase-dependent intracellular signaling pathway. In an attempt to decipher the molecular mechanisms underlying PrP-dependent ethanol effect, we looked for changes in lipid raft features in hippocampus of ethanol-treated wt mice compared to PrP(-/-) mice. Ethanol induced rapid and transient changes of buoyancy of lipid raft-associated proteins in hippocampus of wt but not PrP(-/-) mice suggesting a possible mechanistic link for PrP-dependent signal transduction. Together, our results reveal a hitherto unknown physiological role of PrP on the regulation of NMDAR activity and highlight its crucial role in synaptic functions.
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Petit-Paitel
authors.forename: Baptiste
authors.initials: B
authors.lastname: Ménard
authors.forename: Alice
authors.initials: A
authors.lastname: Guyon
authors.forename: Vincent
authors.initials: V
authors.lastname: Béringue
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Nahon
authors.forename: Nicole
authors.initials: N
authors.lastname: Zsürger
authors.forename: Joëlle
authors.initials: J
authors.lastname: Chabry
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D006224:Cricetinae; D004361:Drug Tolerance; D000431:Ethanol / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D002492:Central Nervous System Depressants; C121001:NR2B NMDA receptor; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases