Extrasynaptic GluN2B-containing N-methyl-d-aspartate (NMDA) receptors homeostatically antagonize long-term potentiation (LTP). A: in control experiments, 3 min of 5-Hz stimulation (delivered at time = 0, ○, n = 14 from 12 animals) produced a small enhancement of synaptic transmission [field excitatory postsynaptic potentials (fEPSPs) were 115 ± 4% of baseline 45 min after 5-Hz stimulation). However, 5 Hz for 3 min delivered in the presence of the GluN2B blocker ifenprodil (5 μM) induced robust LTP (●, fEPSPs were 182 ± 16% of baseline 45 min after 5-Hz stimulation, n = 9 from 8 animals, P < 0.001 compared with controls). Inset: fEPSPs recorded during baseline and 45 min after 5-Hz stimulation in control (left) and ifenprodil (right). Calibration: 2 mV, 2.5 ms. B: summary of the data presented in A and C. Bar graph indicating the mean fEPSP averaged from the last 5 min of experiment in each condition [***P < 0.001 and nonstatistical significance (ns), P > 0.05 compared with untreated controls]. IFEN, ifenprodil; LY, LY341495. C: extrasynaptic metabotropic glutamate receptors do not contribute to the homeostatic pathway. A 10-min bath application of 10 μM mGluR antagonist LY341495 does not rescue LTP. fEPSPs were 113.0% of baseline for control experiments (n = 6 from 5 animals) and 115.1% of baseline for the experiment carried out in the presence of LY341495 (n = 5 from 4 animals); P = 0.9. D: GluN2B-containing NMDA receptors are not required for long-term depression (LTD). fEPSPs were 53.1% (n = 6 from 5 animals) and 46.7% (n = 5 from 4 animals) of baseline values at 60 min after LTD induction in the absence or presence of the ifenprodil 5 μM, respectively; P = 0.73. E: GluN2B-containing NMDA receptors are not required for depotentiation (1 Hz for 15 min delivered 2 min after a high-frequency LTP protocol; 2 times 100 Hz for 1 s). fEPSPs were 109.5% and 108.3% of baseline values at 60 min after depotentiation in the absence (n = 6 from 4 animals) or presence (n = 6 from 4 animals) of the ifenprodil 5 μM, respectively; P = 0.9.