Here we have demonstrated reduced palmitoylation of GluN2B on Cys cluster II in striatal neurons in YAC128 HD mice, and our data using GluN2B palmitoylation-resistant mutants in cultured striatal MSNs strongly suggest this mechanism contributes to accelerated forward trafficking and enhanced extrasynaptic surface expression of 2B-NMDAR in HD. Here, GRIN2B is linked to Huntington disease.