Figure 2. Lateral perforant path LTP depends upon the endocannabinoid 2-AG. A, A 60 min treatment of acute hippocampal slices with JZL184 (1 µm) reduced by 50% activity of the 2-AG degradative enzyme MGL (***p < 0.001 vs veh, t test; n = 9 each). B, Hippocampal slice levels of 2-AG were increased by JZL184 (1 µm; **p < 0.01; n = 10 for veh and JZL184) but decreased by perfusion of THL (10 µm), an inhibitor of the 2-AG synthesizing enzyme DGL-α (***p < 0.001; veh, n = 4; THL, n = 5). C, As determined with fEPSP recordings, the magnitude of LPP potentiation was increased by JZL184 (1 µm) but was not affected by URB597 (1 µm), an inhibitor of FAAH. D, URB597 (1 µm) perfusion for 60 min reduced hippocampal slice FAAH activity (***p < 0.001, n = 10 each). E, LPP input/output curves were comparable for wild-type and MGL-overexpressing transgenics (MGL-tg) as were waveforms for averaged fEPSPs. F, LPP-LTP was reduced in MGL-tg vs wild-type mice (p = 0.016; WT, n = 14; MGL-tg, n = 17). G, H, THL (10 µm) perfused for 60 min significantly reduced LPP-LTP (G; n = 8/group) but not in S-C projections to field CA1 (H; n = 5/group). I, WWL70, an inhibitor of the postsynaptic 2-AG degradative lipase ABHD6, had no effect on LPP-LTP; the modest effect of infusion on baseline responses reflects DMSO in the vehicle. J, Infusion of the CB1 agonist WIN55,212-2 (5 µm) for 1 h prior to, and overlapping, a brief high-frequency stimulation train (arrow) increased the magnitude of LTP relative to levels with veh treatment (p = 0.004; n = 6 for veh group, n = 7 for WIN group); WIN did not significantly influence baseline responses relative to those of the vehicle treatment group. In C and F–J, the horizontal gray bar denotes the period of reagent perfusion; all electrophysiological analyses are from field recordings. Upward arrows indicate the time of LTP-inducing stimulation.