Activation of Group II Metabotropic Glutamate Receptors Promotes LTP Induction at Schaffer Collateral-CA1 Pyramidal Cell Synapses by Priming NMDA Receptors - PubMed (original) (raw)

Characterization of NMDAR subunits that are targeted by group II mGlu receptor subtypes to induce LTP in CA1 pyramidal cells. A, Pharmacologically isolated NMDA currents (NBQX, 25 μ

) evoked by Schaffer collateral stimulation at a holding potential of −70 mV with low extracellular magnesium (0.1 m

) were slightly diminished in the presence of a GluN2B NMDAR subunit antagonist (Ro25–69813, 3 μ

, 20 min), but were strongly reduced after applying a GluN2A NMDAR subunit antagonist (NVP-AAM077, 0.1 μ

, 20 min). Inset, Sample traces of NMDA-EPSCs showing effects of antagonists (****p < 0.0001, *p < 0.05; ANOVA followed by Tukey's post hoc test; F(3, 15) = 179.1). Scale bars, 25 ms and 40 pA. B, LTP is significantly reduced in the presence of antagonists for either the GluN2A (NVP-AAM077, 0.1 μ

, 20 min) or the GluN2B NMDAR subunit (Ro25–69813, 3 μ

, 20 min). C, Quantification of fEPSP slope changes under the conditions presented in B. *p < 0.05 indicates significantly different from slices treated with LY354740 alone (ANOVA followed by Tukey's post hoc test; F(2, 19) = 5.565). D, After bath application of the use-dependent blocker MK-801 (40 μ

, 20 min) to block the synaptic NMDARs selectively, subsequent blocking of GluN2A subunits has no further effect, whereas blocking of GluN2B subunits leads to an additional pronounced reduction in LTP. E, Quantification of fEPSP slope changes under the conditions presented in D. *p < 0.05 indicates significantly different from slices treated with LY354740 alone and MK801 (ANOVA followed by Tukey's post hoc test; F(2, 16) = 3.799). F, Proposed scheme showing the two different pools of NMDARs involved in the induction of LTP, one synaptic including mainly GluN2A subunits and the other extrasynaptic including mainly GluN2B subunits. G, Comparison of group II mGlu-receptor-induced LTP in wild-type, mGlu2 KO, and mGlu3 KO mice shows that only the absence of the mGlu3 receptor reduces LTP. When mGlu2 and mGlu3 receptors are both blocked (LY341495, 4 μ

, 10 min), LTP is prevented. H, Quantification of fEPSP slope changes under the conditions presented in G. *p < 0.05 indicates significantly different from WT mice (ANOVA followed by Tukey's post hoc test; F(2, 17) = 4.09). I, Single train of HFS induces LTP that was not significantly different in WT, mGlu2, and mGlu3 KO slices. J, Quantification of fEPSP slope changes under the conditions presented in I (ANOVA followed by Tukey's post hoc test; F(2, 13) = 0.2183). K, After blockade of the GluN2B NMDAR subunit, LTP was prevented in mGlu3 KO mice and reduced in wild-type and mGlu2 KO mice. L, Quantification of fEPSP slope changes under the conditions presented in K. *p < 0.05 indicates significantly different from WT + Ro25–69813 mice (ANOVA followed by Tukey's post hoc test; F(2, 18) = 7.927). M, Working model illustrating how distinct mGlu2 and mGlu3 receptor localization may lead to preferential modulation of different pools of NMDARs, with only the mGlu3 receptor able to modulate both synaptic and extrasynaptic NMDARs. Scale bars for the field traces: 0.5 mV and 10 ms.