Alterations in N-methyl-D-aspartate receptor sensitivity and magnesium blockade occur early in development in the R6/2 mouse model of Huntington's disease

Amaal J. Starling, Véronique M. André, Carlos Cepeda, Marianne De Lima, Scott H. Chandler, Michael S. Levine

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that affects primarily the striatum and cerebral cortex. A search for the factors that increase the vulnerability of striatal neurons will lead to a better understanding of the pathological cascades of this disease. A current hypothesis for neurodegeneration of striatal medium-sized spiny neurons in HD is an alteration in N-methyl-D-aspartate (NMDA) receptor function. In the present study we examined electrophysiological properties of NMDA receptors in the R6/2 transgenic mouse model. These animals express exon 1 of the human HD gene and present an overt behavioral phenotype at about 5 weeks of age. Whole-cell voltage clamp recordings from acutely dissociated striatal neurons were obtained from three different age groups of transgenic mice (15, 21, and 40 days old) and their littermate controls (WT). In transgenic animals, two groups of neurons were found with respect to NMDA and Mg2+ sensitivity. One group of R6/2 cells displayed responses similar to those of WT, whereas the other showed increased responses to NMDA and decreased Mg2+ sensitivity. These cells were encountered in all age groups. The abnormal sensitivity to NMDA and Mg2+ indicates that NMDA receptor alterations occur very early in development and suggest the presence of constitutively abnormal NMDA receptors. These alterations may contribute to an enhancement of NMDA responses at hyperpolarized membrane potentials that may be a key factor in striatal neuronal dysfunction.

Original languageEnglish (US)
Pages (from-to)377-386
Number of pages10
JournalJournal of Neuroscience Research
Volume82
Issue number3
DOIs
StatePublished - Nov 1 2005

Keywords

  • Dissociated neurons
  • Electrophysiology
  • NMDA
  • Striatum

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Alterations in N-methyl-D-aspartate receptor sensitivity and magnesium blockade occur early in development in the R6/2 mouse model of Huntington's disease'. Together they form a unique fingerprint.

  • Cite this