RNA Based Antagonist of NMDA Receptors

The N-methyl d-aspartate (NMDA) class of ionotropic glutamate receptors plays important roles in learning and memory as well as in a number of neurological disorders including Huntington’s disease and cerebral ischemia. Here, we describe the isolation and characterization of a 2′ F-modified RNA aptamers directed against GluN2A-containing NMDA receptors. By adding a negative selection step toward the closely related AMPA and kainate receptors, the RNA aptamers specifically recognize NMDA receptors with dissociation constants in the nanomolar range. Electrophysiological characterization of these aptamers using rapid perfusion in outside-out patches reveals that they selectively inhibit the GluN2A containing subtype of NMDA receptors with little effect on the AMPA and kainate receptor subtypes. We also demonstrate that this RNA aptamer significantly reduces neurotoxicity in an in vitro model of cerebral ischemia. Given that the RNA based antagonist can be readily modified, it can be used as a tool in targete...