Prion protein is a key determinant of alcohol sensitivity through the modulation of N-methyl-D-aspartate receptor (NMDAR) activity

• Published in: PloS one 2012-04, Vol.7 (4), p.e34691-e34691
• Main Authors: Petit-Paitel, Agnès, Ménard, Baptiste, Guyon, Alice, Béringue, Vincent, Nahon, Jean-Louis, Zsürger, Nicole, Chabry, Joëlle
• Format: Article
• Language: English
• Subjects: Alcohol; Alcoholic beverages; Animal models; Animals; Biology; Cell adhesion & migration; Cells, Cultured; Cellular signal transduction; Central nervous system; Central Nervous System Depressants - pharmacology; Comparative analysis; Cricetinae; Drug Tolerance; Ethanol; Ethanol - pharmacology; Excitatory Postsynaptic Potentials - drug effects; Genetic engineering; Glutamic acid receptors (ionotropic); Hippocampus; Hippocampus - cytology; Hippocampus - drug effects; Humans; Hypotheses; In Vitro Techniques; Intracellular signalling; Kinases; Life Sciences; Lipids; Male; Medicine; Membrane Microdomains - drug effects; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular modelling; N-methyl-D-aspartate; N-Methyl-D-aspartic acid receptors; Neurons and Cognition; Neurophysiology; Oxidative stress; Phosphorylation; Physiological aspects; Physiology; Prion protein; Prion Proteins; Prions (Proteins); Prions - genetics; Prions - metabolism; Protein Transport; Protein-tyrosine kinase; Proteins; Proto-Oncogene Proteins c-fyn - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Receptors, N-Methyl-D-Aspartate - physiology; Reversion; Sensitivity; Signal Transduction; src-Family Kinases - metabolism; Transgenic mice; Trends; Tyrosine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0034691

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.