This Article Full Text Full Text (PDF) Supplemental material Other Versions of this Article: JVI.00486-08v1 82/20/9890    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Trifilo, M. J. Articles by Oldstone, M. B. A. PubMed PubMed Citation Articles by Trifilo, M. J. Articles by Oldstone, M. B. A.

 Previous Article  |  Next Article 

Journal of Virology, October 2008, p. 9890-9899, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.00486-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Scrapie-Induced Defects in Learning and Memory of Transgenic Mice Expressing Anchorless Prion Protein Are Associated with Alterations in the Gamma Aminobutyric Acid-Ergic Pathway ^,

Matthew J. Trifilo,^1, Manuel Sanchez-Alavez,^2, Laura Solforosi,^3, Joie Bernard-Trifilo,³ Stefan Kunz,¹ Dorian McGavern,¹ and Michael B. A. Oldstone^1,4*

Viral-Immunobiology Laboratory, Department of Immunology and Microbial Science,¹ Molecular and Integrative Neurosciences Department,² Department of Immunology,³ Department of Infectology, The Scripps Research Institute, La Jolla, California 92037⁴

Received 5 March 2008/ Accepted 23 July 2008

After infection with RML murine scrapie agent, transgenic (tg) mice expressing prion protein (PrP) without its glycophosphatidylinositol (GPI) membrane anchor (GPI^–/– PrP tg mice) continue to make abundant amounts of the abnormally folded disease-associated PrPres but have a normal life span. In contrast, all age-, sex-, and genetically matched mice with a GPI-anchored PrP become moribund and die due to a chronic progressive neurodegenerative disease by 160 days after RML scrapie agent infection. We report here that infected GPI^–/– PrP tg mice, although free from progressive neurodegenerative disease of the cerebellum and extrapyramidal and pyramidal systems, nevertheless suffer defects in learning and memory, long-term potentiation, and neuronal excitability. Such dysfunction increases over time and is associated with an increase in gamma aminobutyric acid (GABA) inhibition but not loss of excitatory glutamate/N-methyl-D-aspartic acid. Enhanced deposition of abnormally folded infectious PrP (PrPsc or PrPres) in the central nervous system (CNS) localizes with GABAA receptors. This occurs with minimal evidence of CNS spongiosis or apoptosis of neurons. The use of monoclonal antibodies reveals an association of PrPres with GABAA receptors. Thus, the clinical defects of learning and memory loss in vivo in GPI^–/– PrP tg mice infected with scrapie agent may likely involve the GABAergic pathway.

Published ahead of print on 30 July 2008.

Supplemental material for this article may be found at http://jvi.asm.org/.

These authors contributed equally to this work.