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. 2021 Jan 18;118(4):e2017590118. doi: 10.1073/pnas.2017590118

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Fig. 5. — Endocannabinoids mediate presynaptic metaplasticity. (A) Delivering three PDs (25 s total) 1.5 min prior to LTP induction did not alter the magnitude of MC-GC LTP (Control LTP: 200 ± 9% of baseline, n = 7; three PDs 1.5 min pre: 218 ± 13% of baseline, n = 10; Control versus three PDs 1.5 min pre: P = 0.3234, unpaired t test). (B) Delivering 12 PDs (2 min total) 1.5 min prior to LTP induction caused a significant reduction in MC-GC LTP (Control LTP: 195 ± 15% of baseline, n = 9; 12 PDs 1.5 min pre: 127 ± 14% of baseline, n = 7; Control LTP versus 12 PDs 1.5 min pre: P < 0.01, unpaired t test). (C) The 12 PDs protocol did not trigger long-term changes in MC-GC synaptic transmission (98 ± 9% of baseline, n = 7, P = 0.4605, paired t test). (Inset) MC-GC transmission is fully recovered from the 12 PDs protocol by the time of MC-GC LTP induction (gray shadow). (D) The CB1R inverse agonist AM251 (5 μM) blocked the MC-GC LTP dampening induced by 12 PDs (12 PDs 1.5 min pre: 138 ± 11% of baseline, n = 7; AM251: 194 ± 6% of baseline, n = 8; 12 PDs versus AM251: P < 0.05, Mann–Whitney U test). (E) The CB1R competitive antagonist NESS0327 (0.5 μM) also abolished the metaplastic dampening of MC-GC LTP (12 PDs 1.5 min pre: 148 ± 8% of baseline, n = 9; NESS0327: 208 ± 14% of baseline, n = 7; 12 PDs versus NESS0327: P < 0.01, unpaired t test). (F) Bath application of the specific α_i/o inhibitor NF-023 (10 μM) prevented the metaplastic dampening of MC-GC LTP via eCB release prior to LTP induction (12 PDs 1.5 min pre: 158 ± 12% of baseline, n = 6; NF-023: 205 ± 8% of baseline, n = 7; 12 PDs versus NF-023: P < 0.05, Mann–Whitney U test). (G) The dampening of MC-GC LTP was still observed in the presence of the βγ-subunit inhibitor gallein (75 μM) (12 PDs 1.5 min pre: 147 ± 10% of baseline, n = 7; Gallein: 148 ± 4% of baseline, n = 7; 12 PDs versus Gallein: P = 0.9587, unpaired t test). (H) Pairing 12 PDs 1.5 min before LTP induction with three PDs during LTP induction abolishes MC-GC LTP (Control LTP: 204 ± 17% of baseline, n = 7; combined PDs: 112 ± 11% of baseline, n = 8; Control LTP versus combined PDs: P < 0.001, unpaired t test).