Extrasynaptic NR2D-containing NMDARs are recruited to the synapse during LTP of NMDAR-EPSCs.
Long-term potentiation of NMDA-receptor-mediated synaptic transmission (NMDAR-LTP) is a little-understood form of plasticity. In the present study, we investigated whether NMDAR-LTP in the dentate gyrus involves recruitment of extrasynaptic NMDARs, because NMDARs are expressed both synaptically and extrasynaptically with evidence for subtype differences at different locations. We show that before induction of NMDAR-LTP, pharmacological inhibition of glutamate transporters resulted in glutamate spillover from the synapse and activation of extrasynaptic NMDARs. After the induction of NMDAR-LTP, such activation of extrasynaptic NMDARs was absent. Activation of extrasynaptic NMDARs after glutamate uptake inhibition also occurred when synaptic NMDARs were inhibited with MK801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], and this extrasynaptically mediated NMDAR-EPSC was strongly reduced by prior induction of NMDAR-LTP. The extrasynaptic NMDARs were shown to be NR2D-containing, because the activation of extrasynaptic NMDARs by glutamate spillover was prevented by the NR2D-selective antagonists PPDA [(2R*,3S*)-1-(phenanthrenyl-2-carbonyl)piperazine-2,3-dicarboxylic acid] and UBP141. Further studies using selective antagonists for NR2A- and NR2B-containing NMDARs demonstrated that synaptic NMDARs are predominantly NR2A-containing and NR2B-containing receptors, whereas the extrasynaptic NMDARs are complex multimeric receptors with NR2A, NR2B, or NR2D subunits. Our results show that LTP of NMDAR-EPSCs involves movement of NMDARs from an extrasynaptic to a synaptic location and suggest a novel physiological role for extrasynaptic NMDARs.
Harney
Sarah C
SC
Department of Physiology, Trinity College, Dublin 2, Ireland.
Jane
David E
DE
Anwyl
Roger
R
D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D003979:Diazonium Compounds / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D003979:Diazonium Compounds; D018683:Excitatory Amino Acid Agents; D018691:Excitatory Amino Acid Antagonists; C464436:NR2D NMDA receptor; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; C120673:benzyloxyaspartate; C056729:4-(2'-pyridyldithio)benzyldiazoacetate; D001224:Aspartic Acid; D018698:Glutamic Acid; D016291:Dizocilpine Maleate