PMID- 22536327
OWN - NLM
STAT- MEDLINE
DCOM- 20120831
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 4
DP  - 2012
TI  - Prion protein is a key determinant of alcohol sensitivity through the modulation 
      of N-methyl-D-aspartate receptor (NMDAR) activity.
PG  - e34691
LID - 10.1371/journal.pone.0034691 [doi]
LID - e34691
AB  - 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.
FAU - Petit-Paitel, Agnes
AU  - Petit-Paitel A
AD  - Centre National de la Recherche Scientifique, Institut de Pharmacologie 
      Moleculaire et Cellulaire, Valbonne, France.
FAU - Menard, Baptiste
AU  - Menard B
FAU - Guyon, Alice
AU  - Guyon A
FAU - Beringue, Vincent
AU  - Beringue V
FAU - Nahon, Jean-Louis
AU  - Nahon JL
FAU - Zsurger, Nicole
AU  - Zsurger N
FAU - Chabry, Joelle
AU  - Chabry J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120420
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Central Nervous System Depressants)
RN  - 0 (NR2B NMDA receptor)
RN  - 0 (Prion Proteins)
RN  - 0 (Prions)
RN  - 0 (Prnp protein, mouse)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3K9958V90M (Ethanol)
RN  - EC 2.7.10.2 (Fyn protein, mouse)
RN  - EC 2.7.10.2 (Proto-Oncogene Proteins c-fyn)
RN  - EC 2.7.10.2 (src-Family Kinases)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Central Nervous System Depressants/*pharmacology
MH  - Cricetinae
MH  - *Drug Tolerance
MH  - Ethanol/*pharmacology
MH  - Excitatory Postsynaptic Potentials/drug effects
MH  - Hippocampus/cytology/drug effects
MH  - Humans
MH  - In Vitro Techniques
MH  - Male
MH  - Membrane Microdomains/drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Phosphorylation
MH  - Prion Proteins
MH  - Prions/genetics/*metabolism
MH  - Protein Transport
MH  - Proto-Oncogene Proteins c-fyn/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/metabolism/*physiology
MH  - Signal Transduction
MH  - src-Family Kinases/metabolism
PMC - PMC3335038
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/04/27 06:00
MHDA- 2012/09/01 06:00
PMCR- 2012/04/20
CRDT- 2012/04/27 06:00
PHST- 2012/01/09 00:00 [received]
PHST- 2012/03/06 00:00 [accepted]
PHST- 2012/04/27 06:00 [entrez]
PHST- 2012/04/27 06:00 [pubmed]
PHST- 2012/09/01 06:00 [medline]
PHST- 2012/04/20 00:00 [pmc-release]
AID - PONE-D-12-01061 [pii]
AID - 10.1371/journal.pone.0034691 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(4):e34691. doi: 10.1371/journal.pone.0034691. Epub 2012 Apr 20.