We analyzed NMDA receptor subunit mRNAs, proteins, and anchoring proteins in mice transgenic for exon 1 of the HD gene. R6/2 mice had decreased levels of mRNAs encoding ε1 and ε2 NMDA receptor subunits (mouse orthologs of rat NR2A and NR2B subunits), but not the ζ1 subunit (mouse ortholog of NR1), as assessed by gene expression profiling and Northern blotting. In situ hybridization resolved mRNA decreases spatially to the CA1 field of hippocampus. Western blotting revealed decreases in plasma membrane-associated ε1 and ε2 subunits in hippocampus, and decreases in plasma membrane-associated ζ1 subunit in cortex and hippocampus. In addition, PSD-95 and α-actinin-2, proteins essential for anchoring NMDA receptors, were decreased. Finally, we found a decreased level of tyrosine-phosphorylated ε1 subunit, another determinant of NMDA receptor trafficking, in R6/2 hippocampus. Taken together, these data demonstrate multiple levels of NMDA receptor dysregulation, including abnormalities in mRNA expression levels, receptor stoichiometry, protein phosphorylation, and receptor trafficking. © 2003 Elsevier Inc. All rights reserved.