Selective subunit antagonists suggest an inhibitory relationship between NR2B and NR2A-subunit containing N-methyl-D: -aspartate receptors in hippocampal slices.
Glutamate receptors responding to N-methyl-D: -aspartate (NMDA) are involved in neural development, excitotoxicity and neuronal plasticity. Each receptor includes at least two NR2 subunits. Here, we have examined the effects of selective antagonists of NR2A and NR2B subunits (NVP-AAM07 and Ro25-6981 respectively) on the effects of NMDA in the CA1 field of rat hippocampal slices. We have observed that Ro25-6981 potentiates, rather than blocks, the effects of NMD on field EPSPs and paired-pulse interactions (indicators of presynaptic effects) and on postsynaptic depolarisation in hippocampal slices. The NR2A subunit antagonist NVP-AAM077 blocks the effects of NMDA alone, or after potentiation by Ro25-6981. The potentiation of NMDA by Ro25-6981 was not prevented by staurosporine (protein kinase inhibitor), okadaic acid (an inhibitor of serine/threonine protein phosphatases) or anisomycin (protein synthesis inhibitor), but was prevented by cyclosporin A, which inhibits Ca2+/calmodulin-dependent phosphatase 2B [calcineurin]. NMDA-dependent long-term potentiation (LTP) induced by electrical stimulation was not prevented by Ro25-6981 but was prevented by selective blockade of the NR2A subunit. The results suggest that, at both presynaptic and postsynaptic sites in the rat hippocampus, NR2B-subunit-containing receptors limit NMDA receptor function by inhibitory restraint over NR2A-subunit-containing receptors, via calcineurin activation, and that LTP induction critically involves primarily receptors containing the NR2A subunit. Endogenous factors or drugs that modify this NR2B/NR2A interaction could have a major influence on synaptic transmission and plasticity in the brain.
Mallon
Andrew P
AP
Institute of Biomedical & Life Sciences, Division of Neuroscience and Biomedical Systems, West Medical Building, University of Glasgow, Glasgow,
Auberson
Yves P
YP
Stone
Trevor W
TW
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
C498554:5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D011500:Protein Synthesis Inhibitors; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D019703:Calcineurin