Figure 1. Modulators differentially potentiate NMDAR-mediated EPSCs after MK-801 block of synaptic NMDARs. A, Example of progressive MK-801 block during evoked stimulation and subsequent recovery of INMDAR. Synaptic receptor blockade was accomplished by delivering low-frequency presynaptic stimulation (0.1 Hz) in the presence of MK-801 (5 μm). The gray bar indicates the time period when MK-801 was applied; the open bars show application of regular extracellular saline solution (bath) or of elevated Ca2+ (4Ca2+). The recovered INMDAR in regular external bath or 4 mm Ca2+ was sampled 2–3 min after MK-801 wash off. The amplitude of INMDAR is plotted against the stimulus episode. Inset, Superimposed initial (a), the basal recovered INMDAR (b), and the recovered current in 4 mm Ca2+ (c) shown from the corresponding time point in the amplitude–stimulus plot. B, C, Similar to A, with PDBu (1 μm) (B) or FSK (50 μm) (C) applied during the 2 min interval after MK-801 wash off. D1, Summary of synaptic INMDAR potentiation by modulators after synaptic receptor blockade. The residual INMDAR after MK-801 block is set as 100% (PDBu: 526 ± 71%, n = 10, *p < 0.00007; FSK: 184 ± 25%, n = 7; 4 mm Ca2+: 150 ± 17%, n = 8; statistical comparison is with the control: 147 ± 12%, n = 8). D2, Comparison of the percentage INMDAR recovery (Δ recovered current = recovered current − residual current) after modulator treatment. The Δ recovered INMDAR is normalized to the initial INMDAR. The initial INMDAR is set to 100% (PDBu: 20 ± 5%, n = 10, *p < 0.005; FSK: 3.2 ± 0.8%, n = 7; 4 mm Ca2+: 3.0 ± 0.4%, n = 8; statistical comparison is with the control: 1.6 ± 0.5%, n = 8). E, Synaptic NMDAR blockade did not affect IAMPAR potentiation by modulators. E1, Sample traces of IAMPAR in 4 mm Ca2+, PDBu, and FSK (gray); traces are superimposed on their corresponding initial EPSC (black). The percentage potentiation of EPSCs by modulators is summarized in E2 (PDBu: 230 ± 23% of initial IAMPAR, n = 10, *p < 0.0002; FSK: 157 ± 19% of the initial IAMPAR, n = 7, **p < 0.02; 4 mm Ca2+: 163 ± 8% of the initial IAMPAR, n = 7, ***p < 0.002; all statistics are compared with the control: 83 ± 8%, n = 8). Error bars indicate SEM.