Moreover, we provide evidence that the transcriptional dysregulation that results—at least in part—from esNMDAR activity in HD model mice can be rescued with the NMDAR open-channel blocker, memantine26, or the small molecule TwinF interface inhibitor, FP802, that abolishes excitotoxic signaling by disruption of the interaction between esNMDARs and transient receptor potential cation channel subfamily M member 4 (TRPM4) channels8,23,27,28. Here, TRPM4 is linked to Huntington disease.