Distinct NMDA Receptor Subpopulations Contribute to Long-Term Potentiation and Long- Term Depression Induction

Abstract

Long-term potentiation (LTP) and long-term depression (LTD) are persistent modifications of synaptic strength that have been implicated in learning, memory, and neuronal development. Despite their opposing effects, both forms of plasticity can be triggered by the activation of NMDA receptors. One mechanism proposed for this bidirectional response is that the specific patterns of afferent stimulation producing LTP and LTD activate to different degrees a uniform receptor population. A second possibility is that these patterns activate separate receptor subpopulations composed of different NMDA receptor (NR) subunits. To test this hypothesis we examined the inhibition of LTP and LTD by a series of competitive NMDA receptor antagonists that varied in their affinities for NR2A/B and NR2C/D subunits. The potency for the inhibition of LTP compared with inhibition of LTD varied widely among the agents. Antagonists with higher affinity for NR2A/B subunits relative to NRC/D subunits showed more potent inhibition of LTP than of LTD. D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid, which binds to NR2A/B with very high affinity relative to NR2C/D, showed an approximately 1000-fold higher potency for LTP than for LTD. These results show that distinct subpopulations of NMDA receptors characterized by different NR2 subunits contribute to the induction mechanisms of potentiation and depression.

Extrasynaptic NR2D-Containing NMDARs Are Recruited to the Synapse during LTP of NMDAR-EPSCs

“…However, the observed differential PPDA sensitivity can be attributed to the expression of distinct NMDAR subtypes. The IC 50 value for PPDA at extrasynaptic NMDARs found in the present study is very similar to the K i of ϳ0.1 M for the action of PPDA at NR1A/ NR2D recombinant receptors shown in previous studies (Hrabetova et al, 2000;Feng et al, 2004), and strongly supports the identification of extrasynaptic NMDARs as NR2D-containing receptors.…”

“…PPDA inhibited control synaptic NMDAR- EPSCs only at very high concentrations of 5-10 M (40% inhibition at 5 M, n ϭ 5 and 65% inhibition at 10 M, n ϭ 6). PPDA is nonselective at such high concentrations, inhibiting NR2A and NR2B as well as NR2D (Hrabetova et al, 2000;Feng et al, 2004). The relative insensitivity of synaptic NMDARs to PPDA demonstrates an absence of NR2D-containing NMDARs at the synapse, with the inhibition of synaptic NMDAR-EPSCs at high concentrations of PPDA being attributable to a nonselective action of PPDA on NR1/NR2A-or NR1/NR2B-containing receptors.…”

NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity

“…PPDA was reported as a selective NR2D competitive antagonist at low concentrations, as we used, with an IC50 value of around 0.1 mM. 23,24,29 Although, PPDA was also reported as an antagonist of NR2C, in agreement with the absence of NR2C mRNA in our cultured cortical neurons, N2RC was only detected in the cerebellum, thalamus and olfactory bulb. 30 At low concentration, PPDA completely prevented the worsening effect of tPA on NMDA-induced neuronal death.…”

Hepatocyte growth factor as an enhancer of nmda currents and synaptic plasticity in the hippocampus

“…However, it seems inconsistent that HGF failed to affect LTD, which would also require NMDA receptor activation. This may be due to a difference in the subtypes of the NR2 subunit since it has been suggested that NR2A and/or NR2B work for LTP while NR2C and/or NR2D work for LTD (Hrabetova et al, 2000). If the effect of HGF on the NMDA receptor is mediated mainly by PKC, the selectivity for LTP is consistent with the selectivity of the PKC-induced phosphorylation of NR2A and NR2B, and not of NR2C and NR2D (Mori et al, 1993;Liao et al, 2001).…”