| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1Kinsmen Laboratory, Department of Psychiatry, 2Brain Research Centre, 3Centre for Molecular Medicine and Therapeutics and Department of Medical Genetics, 4Division of Neurology, Department of Medicine, University of British Columbia, Vancouver BC V6T 1Z3, Canada
Submitted 26 March 2004; accepted in final form 3 June 2004
Huntington disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract near the N terminus of the protein huntingtin, leading to dramatic loss of striatal medium-sized spiny GABAergic projection neurons (MSNs). Evidence suggests overactivation of N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) contributes to selective degeneration of MSNs in HD. Striatal MSNs are enriched in NR2B, and whole cell current and excitotoxicity mediated predominantly by the NR2B subtype of NMDARs is increased with expression of mutant huntingtin in transfected cell lines and striatal MSNs from mice models. To test whether synaptic NMDAR current is altered by mutant huntingtin expression, we recorded striatal MSN excitatory postsynaptic currents (EPSCs) evoked by stimulation of cortical afferents in corticostriatal slices from YAC72 mice and their wild-type (WT) littermates at age 21–31 days. The ratio of NMDAR- to AMPAR-mediated EPSC amplitude was significantly increased in YAC72 compared to WT mice. Furthermore, using a paired-pulse stimulation protocol as a measure of presynaptic glutamate release probability, we found no significant differences between YAC72 and WT striatal MSN responses. These data suggest selective potentiation of postsynaptic NMDAR activity at corticostriatal synapses in YAC72 mice. Measurements of EPSC decay kinetics, as well as the effects of NR2B-subtype selective antagonists and glycine concentration on EPSC amplitude, are consistent with the majority of postsynaptic NMDARs being triheteromers of NR1/NR2A/NR2B in both WT and YAC72 mice. Together with previous results, our data suggest that enhanced activity of NR2B-containing NMDARs is one of the earliest changes leading to neuronal degeneration in HD.
This article has been cited by other articles:
|
|
 |
|
  A. J. Milnerwood and L. A. Raymond Corticostriatal synaptic function in mouse models of Huntington's disease: early effects of huntingtin repeat length and protein load J. Physiol., December 15, 2007; 585(3): 817 - 831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. B. Fernandes, K. G. Baimbridge, J. Church, M. R. Hayden, and L. A. Raymond Mitochondrial Sensitivity and Altered Calcium Handling Underlie Enhanced NMDA-Induced Apoptosis in YAC128 Model of Huntington's Disease J. Neurosci., December 12, 2007; 27(50): 13614 - 13623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. T. Moyer, J. A. Wolf, and L. H. Finkel Effects of Dopaminergic Modulation on the Integrative Properties of the Ventral Striatal Medium Spiny Neuron J Neurophysiol, December 1, 2007; 98(6): 3731 - 3748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Logan, J. G. Partridge, J. A. Matta, A. Buonanno, and S. Vicini Long-Lasting NMDA Receptor-Mediated EPSCs in Mouse Striatal Medium Spiny Neurons J Neurophysiol, November 1, 2007; 98(5): 2693 - 2704. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Milnerwood, D. M. Cummings, G. M. Dallerac, J. Y. Brown, S. C. Vatsavayai, M. C. Hirst, P. Rezaie, and K. P.S.J. Murphy Early development of aberrant synaptic plasticity in a mouse model of Huntington's disease Hum. Mol. Genet., May 15, 2006; 15(10): 1690 - 1703. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
