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Sci. Signal., 13 May 2008
Vol. 1, Issue 19, p. ec174
[DOI: 10.1126/stke.119ec174]

EDITORS' CHOICE

Neuroscience Prion Protein Protection

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

When cellular prion protein (PrPc) misfolds into the scrapie form (PrPSc), it is responsible for transmissible spongiform encephalopathies; however, the physiological functions of PrPc remain unclear. Studies with mice in which the gene encoding PrP is disrupted revealed that PrPc may play a neuroprotective role, as well as contribute to spatial learning. Khosravani et al. found that neuronal excitability was increased in hippocampal slices from the PrP-null mice--with increased action potential firing in response to a single stimulus, decreased minimal stimulus required to evoke an action potential, and decreased stimulus intensity required to reach a maximum response. This increased neuronal excitability was blocked by bath application of an antagonist of N-methyl-D-aspartate (NMDA)-type glutamate receptors. Primary cultures of PrP-null hippocampal neurons had NMDA receptor-mediated currents with longer decay times and larger amplitudes, and transfection of PrP into the cells restored wild-type kinetics to the response to NMDA, suggesting that PrP acutely regulates NMDA receptor signaling and that loss of PrP was not causing a developmental defect. NMDA receptors may be composed of various subunits with different electrophysiological and pharmacological properties. A comparison of the response of the cultured hippocampal neurons to application of an NR2B-selective inhibitor suggested that the wild-type neurons had a larger proportion of NR2B-containing NMDA receptors. The electrophysiological properties of the NMDA-stimulated responses in the PrP-null neurons were similar to those obtained in studies with heterologously expressed NR2D-containing NMDA receptors. Although the distribution and abundance of NR2D subunits appeared unchanged in the hippocampus of the wild-type and PrP-null mice, knockdown of the NR2D subunit by siRNA techniques in the cultured PrP-null neurons accelerated the decay kinetics and reduced the amplitude of the response to application of NMDA. PrPc and NR2D subunits coimmunoprecipitated from wild-type mouse hippocampus, suggesting that PrPc may interact with the NR2D-containing receptors and inhibit their activity. Thus, in the absence of PrPc, these NR2D-containing receptors contribute more to the response to glutamate--leading to a hyperexcitable phenotype. Both in vivo (focal injection) and in culture (bath application), the absence of PrPc was associated with increased neuronal death under conditions in which NMDA is toxic. Thus, one function of PrPc appears to be to limit the contribution of NR2D-containing NMDA receptors to hippocampal responses to glutamate signals and thus limit hippocampal excitability.

H. Khosravani, Y. Zhang, S. Tsutsui, S. Hameed, C. Altier, J. Hamid, L. Chen, M. Villemaire, Z. Ali, F. R. Jirik, G. W. Zamponi, Prion protein attenuates excitotoxicity by inhibiting NMDA receptors. J. Cell Biol. 181, 551-565 (2008). [Abstract] [Full Text]

Citation: N. R. Gough, Prion Protein Protection. Sci. Signal. 1, ec174 (2008).



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