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. 2018 Apr 18;24(8):1206–1219. doi: 10.1038/s41380-018-0034-4

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — Blockade of CB1R in Pyr-WT phenocopies LTP and LTD alterations in Pyr-KO. a Cartoon illustrating synthesis and retrograde release of eCBs following a plasticity-inducing stimulus. Synaptic stimulation [1] triggers release of glutamate [2] which binds to postsynaptic AMPAR, NMDAR and Group I mGluRs [3]. Signaling downstream of NMDAR and Group I mGluRs elicits endogenous cannabinoid synthesis (eCBs) and release [4, 5], and binding to presynaptic CB1 receptor (CB1R) [6]. CB1R activation decreases neurotransmitter release [7]. Application of AM251 (a CB1R inverse agonist) depresses CB1R activation [8] and generates higher than normal glutamate release [9]. b LTD (1 Hz) of CA3-CA1 synapses is abolished in Pyr-WT with addition of 5 µM AM251 (107.4 ± 0.57 % baseline; n = 10 slices/4 mice); 1 Hz stimulation in Pyr-KO in the presence of AM251 resulted in the post-induction fEPSP slope of 99.2 ± 0.63 % baseline (n = 8 slices/4 mice). c LTP in Pyr-WT in the presence of 5 µM AM251 (174.1 ± 1.2 %; n = 13 slices/5 mice) increases relative to LTP in control conditions (146.19 ± 1.3 % from Fig. 2a, p < 0.001, 2-Way RM Anova), and even slightly surpasses the LTP measured in Pyr-KO in the presence of 5 µM AM251 (165.8 ± 1.5%; n = 8 slices/3 mice; p < 0.001, 2-Way RM Anova). d Summary of LTP and LTD vs. frequency of induction in Pyr-WT vs. Pyr-KO in presence of 5 µM AM251. Absence of LTD is now evident in both Pyr-KO and Pyr-WT. e PPR in AM251. Differences in PPR in Pyr-WT vs. Pyr-KO after induction of LTD and LTP seen in control conditions (Fig. 2e) are abolished in the presence of AM251.PPR after 1 Hz: Pyr-WT 0.99 ± 0.01 (n = 10 slices/ 4 mice) vs. Pyr-KO, 1.01 ± 0.01 (n = 8 slices/ 4 mice); p = 0.02. PPR after 4 × 100 Hz: Pyr-WT: 0.95 ± 0.01 (n = 13 slices, 5 mice) vs. Pyr-KO: 0.97 ± 0.01 (n = 8 slices, 3 mice); p = 0.015. Test: 2-Way RM Anova. Means are averages from 20 to 90 min post-induction. Insets: fEPSP trace examples from Pyr-WT and Pyr-KO slices before (gray line) or after induction (black line) of LTD (b) or LTP (c); each trace is average of 30 individual traces taken at baseline or at 75–90 min post-induction.