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Prion protein attenuates excitotoxicity by inhibiting NMDA receptors

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

It is well established that misfolded forms of cellular prion protein (PrP [PrP^C]) are crucial in the genesis and progression of transmissible spongiform encephalitis, whereas the function of native PrP^C remains incompletely understood. To determine the physiological role of PrP^C, 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 PrP^C. 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 PrP^C 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, -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.

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