Role of NR2B-type NMDA receptors in selective neurodegeneration in Huntington disease

Li, Lijun; Fan, Mannie; Icton, Carolyn D.; Chen, Nansheng; Leavitt, Blair R.; Hayden, Michael R.; Murphy, Tim H.; Raymond, Lynn A.

doi:10.1016/j.neurobiolaging.2003.04.003

« Previous Next »Neurobiology of Aging
Volume 24, Issue 8 , Pages 1113-1121, December 2003

Role of NR2B-type NMDA receptors in selective neurodegeneration in Huntington disease

Lijun Li
- Kinsmen Laboratories, Department of Psychiatry, University of British Columbia, 4N3-2255 Westbrook Mall, Vancouver, BC, Canada V6T 1Z3
Mannie Fan
- Kinsmen Laboratories, Department of Psychiatry, University of British Columbia, 4N3-2255 Westbrook Mall, Vancouver, BC, Canada V6T 1Z3
Carolyn D. Icton
- Kinsmen Laboratories, Department of Psychiatry, University of British Columbia, 4N3-2255 Westbrook Mall, Vancouver, BC, Canada V6T 1Z3
Nansheng Chen
- Kinsmen Laboratories, Department of Psychiatry, University of British Columbia, 4N3-2255 Westbrook Mall, Vancouver, BC, Canada V6T 1Z3
Blair R. Leavitt
- Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V5Z 4H4
Michael R. Hayden
- Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V5Z 4H4
Tim H. Murphy
- Kinsmen Laboratories, Department of Psychiatry, University of British Columbia, 4N3-2255 Westbrook Mall, Vancouver, BC, Canada V6T 1Z3
Lynn A. Raymond
- Kinsmen Laboratories, Department of Psychiatry, University of British Columbia, 4N3-2255 Westbrook Mall, Vancouver, BC, Canada V6T 1Z3
- Corresponding author. Tel.: +1-604-822-0723; fax: +1-604-822-7981.

Received 10 December 2002; received in revised form 10 March 2003; accepted 24 April 2003.

Abstract

N-Methyl-d-aspartate receptor (NMDAR)-mediated excitotoxicity has been proposed to play a role in Huntington disease (HD), caused by expansion of a polyglutamine tract in the protein huntingtin. HD is characterized by selective neurodegeneration most severely affecting striatal medium-sized spiny projection neurons (MSNs), where expression of the NMDAR subunit NR2B is increased relative to other NR2 subunits. Here, we review our data that NR2B-type NMDAR currents are selectively potentiated by mutant huntingtin in transfected non-neuronal cells and acutely dissociated striatal MSNs from the YAC72 transgenic mouse model of HD. As well, we report increased striatal MSN NMDAR-mediated synaptic currents in corticostriatal slice recordings from YAC72 compared with wild-type mice. This effect was associated with a larger NMDAR- to AMPAR-mediated current ratio, suggesting specific potentiation of postsynaptic NMDARs. Enhanced NMDAR current likely involves increased surface receptor numbers or activity, since we observed no differences between genotypes in striatal NR2B expression. Potentiation of NR2B-containing NMDAR current in striatal MSNs expressing mutant huntingtin may help explain the exquisite vulnerability of these neurons to degeneration in HD.

Keywords: Excitotoxicity, Striatum, Glutamate, Synaptic transmission, Electrophysiology, Transgenic mice, Patch clamp recording, Brain slice, NR2A, AMPA receptor, Western blot