The role of GluN2B-containing NMDA receptors in short- and long-term fear recall

N-methyl-n-aspartate (NMDA) receptors are crucial synaptic elements in long-term memory formation, including the associative learning of fearful events. Although NMDA blockers were consistently shown to inhibit fear memory acquisition and recall, the clinical use of general NMDA blockers is hampered by their side effects. Recent studies revealed significant heterogeneity in the distribution and neurophysiological characteristics of NMDA receptors with different GIuN2 (NR2) subunit composition, which may have differential role in fear learning and recall. To investigate the specific role of NMDA receptor subpopulations with different GIuN2 subunit compositions in the formation of lasting traumatic,memories, we contrasted the effects of general NMDA receptor blockade with GIuN2A-, GIuN2B-, and GIuN2C/D subunit selective antagonists (MK-801, PEAQX, Ro256981, PPDA, respectively). To investigate acute and lasting consequences, behavioral responses were investigated 1 and 28 days after fear conditioning. We found that MK-801 (0.05 and 0.1 mg/kg) decreased fear recall at both time points. GIuN2B receptor subunit blockade produced highly similar effects, albeit efficacy was somewhat smaller 28 days after fear conditioning. Unlike MK-801, Ro25-6981 (3 and 10 mg/kg) did not affect locomotor activity in the open-field. In contrast, GIuN2A and GIuN2C/D blockers (6 and 20 mg/kg PEAQX; 3 and 10 mg/kg PPDA, respectively) had no effect on conditioned fear recall at any time point and dose. This sharp contrast between GIuN2B- and other subunit-containing NMDA receptor function indicates that GIuN2B receptor subunits are intimately involved in fear memory formation, and may provide a novel pharmacological target in post-traumatic stress disorder or other fear-related disorders.