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.

Molecular mechanisms underlying alcohol-drinking behaviours

“…Cholesterol content varies across brain regions, and thus alcohol may regulate a broad range of cell-surface receptor-induced signalling in a brain region-specific manner by changing the structure, fluidity and composition of membrane lipids, including cholesterol-enriched rafts. Several studies have started to address this possibility in cells 184, 185 and in vivo 30, 186, 187 . However, data from animal models of alcohol consumption are sparse 30 , in part owing to technical limitations.…”

From Signaling Pathways to Behavior

“…An intriguing new signaling molecule, Prion protein (PrP), was recently reported to play a role in alcohol intoxication and the development of acute tolerance (Petit-Paitel et al, 2012). Specifically, Petit-Paitel et al observed that the duration of LORR was longer in transgenic PrP KO mice and shorter in PrP-overexpressing mice as compared to WT mice (Petit-Paitel et al, 2012).…”

“…Specifically, Petit-Paitel et al observed that the duration of LORR was longer in transgenic PrP KO mice and shorter in PrP-overexpressing mice as compared to WT mice (Petit-Paitel et al, 2012). Petit-Paitel et al also found that PrP contributes to the development of acute tolerance to the inhibitory actions of NMDAR by alcohol in a mechanism that requires Fyn-mediated phosphorylation of the NR2B subunit of the NMDAR (GluN2B).…”

“…Lipid rafts, cholesterol-and glycosphingolipid-enriched microdomains in the cell membrane, serve as a platform for the temporal and spatial activation of signaling cascades (Allen, Halverson-Tamboli, & Rasenick, 2007). Interestingly, the study by Petit-Paitel and colleagues, discussed in "Molecular Mechanisms Underlying Alcohol-Mediated Stress and Anxiety," suggests that PrP controls the redistribution of lipid-raft composition in response to an acute administration of alcohol (Petit-Paitel et al, 2012). We have demonstrated that binge drinking of alcohol following long-term repeated cycles of alcohol exposure and withdrawal induced a movement of PTPα into lipid-raft domains (Gibb, Hamida, et al, 2011).…”

Overcoming barriers and thresholds – signaling of oligomeric Aβ through the prion protein to Fyn

“…The need to answer this pressing question has also been noted by others [10], and has led to a situation where several authors of recent papers indicated this knowledge gap in schematic models either with conspicuous question marks or by omitting labels for the corresponding molecular entity altogether (e.g., schematic drawings in [20-22]).…”