NMDA receptor function in mouse models of Huntington disease

J Neurosci Res. 2001 Nov 15;66(4):525-39. doi: 10.1002/jnr.1244.


Huntington disease (HD) is an autosomal dominant disorder in which degeneration of medium-sized spiny striatal neurons occurs. The HD gene and the protein it encodes, huntingtin, have been identified but their functions remain unknown. Transgenic mouse models for HD have been developed and we examined responses of medium-sized striatal neurons recorded in vitro to application of N-methyl-D-aspartate (NMDA) in two of these. The first model (R6/2) expresses exon 1 of the human HD gene with approximately 150 CAG repeats. In the R6/2 an enhancement of currents induced by selective activation of NMDA receptors as well as an enhancement of intracellular Ca(2+) flux occurred in both presymptomatic and symptomatic mice. These alterations appeared specific for the NMDA receptor because alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated currents were reduced in symptomatic R6/2s. In R6/2 animals there were parallel increases in NMDA-R1 and decreases in NMDA-R2A/B subunit proteins as established by immunohistochemistry. The second model (YAC72) contains human genomic DNA spanning the full-length gene and all its regulatory elements with 72 CAG repeats. The phenotypical expression of the disorder develops more gradually than in the R6/2. In YAC72 mice we found similar but less marked increases in responses of medium-sized striatal neurons to NMDA. These findings indicate that alterations in NMDA receptor function may predispose striatal neurons to excitotoxic damage, leading to subsequent neuronal degeneration and underscore the functional importance of NMDA receptors in HD.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Calcium Channels / drug effects
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Calcium Signaling / drug effects
  • Calcium Signaling / genetics
  • Disease Models, Animal
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Huntington Disease / physiopathology
  • Immunohistochemistry
  • Ion Channels / drug effects
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Neurologic Mutants
  • Mice, Transgenic
  • Mutation / physiology*
  • N-Methylaspartate / pharmacology
  • Neostriatum / drug effects
  • Neostriatum / metabolism*
  • Neostriatum / physiopathology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology


  • Calcium Channels
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Ion Channels
  • NMDA receptor A1
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • N-methyl D-aspartate receptor subtype 2A