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J. Cell Biol. 181 (3): 551-565

Copyright © 2008 by the Rockefeller University Press.

Article

Prion protein attenuates excitotoxicity by inhibiting NMDA receptors

Houman Khosravani1, Yunfeng Zhang1, Shigeki Tsutsui2, Shahid Hameed1, Christophe Altier1, Jawed Hamid1, Lina Chen1, Michelle Villemaire2, Zenobia Ali2, Frank R. Jirik2, , and Gerald W. Zamponi1

1 Department of Physiology and Biophysics, Hotchkiss Brain Institute, and 2 Department of Biochemistry and Molecular Biology, McCaig Institute for Bone and Joint Health, University of Calgary, Calgary T2N4N1, Canada

Correspondence to Gerald W. Zamponi: zamponi{at}ucalgary.ca

Abstract: It is well established that misfolded forms of cellular prion protein (PrP [PrPC]) are crucial in the genesis and progression of transmissible spongiform encephalitis, whereas the function of native PrPC remains incompletely understood. To determine the physiological role of PrPC, we examine the neurophysiological properties of hippocampal neurons isolated from PrP-null mice. We show that PrP-null mouse neurons exhibit enhanced and drastically prolonged N-methyl-D-aspartate (NMDA)–evoked currents as a result of a functional upregulation of NMDA receptors (NMDARs) containing NR2D subunits. These effects are phenocopied by RNA interference and are rescued upon the overexpression of exogenous PrPC. The enhanced NMDAR activity results in an increase in neuronal excitability as well as enhanced glutamate excitotoxicity both in vitro and in vivo. Thus, native PrPC mediates an important neuroprotective role by virtue of its ability to inhibit NR2D subunits.

Abbreviations used in this paper: aCSF, artificial cerebrospinal fluid; APV, aminophosphonovaleric acid; DIV, day in vitro; fEPSP, field excitatory postsynaptic potential; GABA, {gamma}-aminobutyric acid; mEPSC, miniature excitatory postsynaptic current; mIPSC, miniature inhibitory postsynaptic current; NMDA, N-methyl-D-aspartate; NMDAR, NMDA receptor; PrP, prion protein; TSE, transmissible spongiform encephalopathy; TTX, tetrodotoxin; WT, wild type.

© 2008 Khosravani et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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