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Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling

Abstract

Cognitive impairment is one of the most important negative consequences associated with cannabis consumption. We found that CB1 cannabinoid receptor (CB1R) activation transiently modulated the mammalian target of rapamycin (mTOR)/p70S6K pathway and the protein synthesis machinery in the mouse hippocampus, which correlated with the amnesic properties of delta9-tetrahydrocannabinol (THC). In addition, non-amnesic doses of either the mTOR blocker rapamycin or the protein synthesis inhibitor anisomycin abrogated the amnesic-like effects of THC, pointing to a mechanism involving new protein synthesis. Moreover, using pharmacological and genetic tools, we found that THC long-term memory deficits were mediated by CB1Rs expressed on GABAergic interneurons through a glutamatergic mechanism, as both the amnesic-like effects and p70S6K phosphorylation were reduced in GABA-CB1R knockout mice and by NMDA blockade.

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Figure 1: Modulation of the mTOR pathway by cannabinoids acting on CB1R.
Figure 2: Temporal modulation of protein translation machinery and mTOR involvement.
Figure 3: The amnesic-like effects of THC are blocked by the administration of rapamycin or anisomycin.
Figure 4: THC effects of p70S6K and S6 occur at the postsynaptic level and not in the GABAergic neurons.
Figure 5: The THC-mediated activation of mTOR and the memory impairment are sensitive to NMDA receptor blockade.
Figure 6: THC effects on mTOR signaling and cognitive function depend on CB1R localized in GABAergic neurons.

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Acknowledgements

We thank C. Fernández-Avilés for expert technical assistance, J. Bertran-Gonzalez for advice in immunohistochemical techniques and the Laboratori de Neurofarmacologia for helpful discussion. This study was supported by grants from the European Commission (CANSIGWITH (MIRG-6-CT-2005-014856) to A.O. and NEWMOOD (LSHM-CT-2004-503474) and GENADDICT (LSHM-CT-2004-05166) to R.M.), the Spanish Ministry of Health (FIS PI041526) to A.O., the Spanish Ministry of Science and Innovation (Consolider-C #SAF2007-64062), Generalitat de Catalunya (2005SGR00131) and ICREA Academia to R.M. A.O. is a recipient of a Ramon y Cajal award from the Spanish Ministry of Education and Culture, E.P. is a recipient of a predoctoral fellowship from the Spanish Ministry of Education and Culture and A.B.-G. is a recipient of a fellowship from La Caixa.

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E.P. conducted the biochemical, immunohistochemical and behavioral experiments and wrote the manuscript. G.M. provided CB1 conditional knockout mice. A.B.-G. conducted behavioral experiments and wrote the manuscript. B.L. provided CB1 conditional knockout mice. R.M. funded the project, participated in experimental design and wrote the manuscript. A.O. conceptualized, supervised and funded the project, participated in experimental design, and wrote the manuscript.

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Correspondence to Andrés Ozaita.

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Puighermanal, E., Marsicano, G., Busquets-Garcia, A. et al. Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nat Neurosci 12, 1152–1158 (2009). https://doi.org/10.1038/nn.2369

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