title: The role of GluN2B-containing NMDA receptors in short- and long-term fear recall.
abstract: N-methyl-d-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 GluN2 (NR2) subunit composition, which may have differential role in fear learning and recall. To investigate the specific role of NMDA receptor subpopulations with different GluN2 subunit compositions in the formation of lasting traumatic memories, we contrasted the effects of general NMDA receptor blockade with GluN2A-, GluN2B-, and GluN2C/D subunit selective antagonists (MK-801, PEAQX, Ro25-6981, PPDA, respectively). To investigate acute and lasting consequences, behavioral responses were investigated 1 and 28days after fear conditioning. We found that MK-801 (0.05 and 0.1mg/kg) decreased fear recall at both time points. GluN2B receptor subunit blockade produced highly similar effects, albeit efficacy was somewhat smaller 28days after fear conditioning. Unlike MK-801, Ro25-6981 (3 and 10mg/kg) did not affect locomotor activity in the open-field. In contrast, GluN2A and GluN2C/D blockers (6 and 20mg/kg PEAQX; 3 and 10mg/kg PPDA, respectively) had no effect on conditioned fear recall at any time point and dose. This sharp contrast between GluN2B- and other subunit-containing NMDA receptor function indicates that GluN2B 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.
authors.affiliation: Institute of Experimental Medicine, Department of Behavioral Neuroscience, P.O. Box 67, H-1450 Budapest, Hungary. Electronic address: mikics.eva@koki.mta.hu.
authors.forename: Eva
authors.initials: E
authors.lastname: Mikics
authors.affiliation: Institute of Experimental Medicine, Department of Behavioral Neuroscience, P.O. Box 67, H-1450 Budapest, Hungary.
authors.forename: Mate
authors.initials: M
authors.lastname: Toth
authors.affiliation: Institute of Experimental Medicine, Department of Behavioral Neuroscience, P.O. Box 67, H-1450 Budapest, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Biro
authors.affiliation: Institute of Experimental Medicine, Department of Behavioral Neuroscience, P.O. Box 67, H-1450 Budapest, Hungary.
authors.forename: Biborka
authors.initials: B
authors.lastname: Bruzsik
authors.affiliation: Institute of Experimental Medicine, Department of Behavioral Neuroscience, P.O. Box 67, H-1450 Budapest, Hungary.
authors.forename: Boglarka
authors.initials: B
authors.lastname: Nagy
authors.affiliation: Institute of Experimental Medicine, Department of Behavioral Neuroscience, P.O. Box 67, H-1450 Budapest, Hungary.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Haller
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004597:Electroshock; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology*; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D011939:Mental Recall / Q000187:drug effects / Q000502:physiology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor; C432823:NR2C NMDA receptor; C464436:NR2D NMDA receptor
keywords: Conditioned fear; Fear recall; GluN2B antagonist; N-methyl-d-aspartate receptor; Post-traumatic stress disorder