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

Emma Puighermanal; Giovanni Marsicano; Arnau Busquets-Garcia; Beat Lutz; Rafael Maldonado; Andrés Ozaita

doi:10.1038/nn.2369

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

Nat Neurosci. 2009 Sep;12(9):1152-8. doi: 10.1038/nn.2369. Epub 2009 Aug 2.

Authors

Emma Puighermanal¹, Giovanni Marsicano, Arnau Busquets-Garcia, Beat Lutz, Rafael Maldonado, Andrés Ozaita

Affiliation

¹ Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.

PMID: 19648913
DOI: 10.1038/nn.2369

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anisomycin / pharmacology
Central Nervous System Agents / pharmacology
Cognition / drug effects
Cognition / physiology
Dronabinol
Glutamic Acid / genetics
Glutamic Acid / metabolism
Hippocampus / drug effects
Hippocampus / physiology*
Male
Memory / drug effects
Memory / physiology*
Memory Disorders / chemically induced
Memory Disorders / drug therapy
Memory Disorders / physiopathology
Mice
Mice, Knockout
Neurons / drug effects
Neurons / physiology
Protein Kinases / metabolism
Protein Synthesis Inhibitors / pharmacology
Receptor, Cannabinoid, CB1 / genetics
Receptor, Cannabinoid, CB1 / metabolism*
Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate / metabolism
Ribosomal Protein S6 Kinases, 70-kDa / genetics
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
Signal Transduction
Sirolimus / pharmacology
TOR Serine-Threonine Kinases
gamma-Aminobutyric Acid / genetics
gamma-Aminobutyric Acid / metabolism

Substances

Central Nervous System Agents
Protein Synthesis Inhibitors
Receptor, Cannabinoid, CB1
Receptors, N-Methyl-D-Aspartate
Glutamic Acid
gamma-Aminobutyric Acid
Anisomycin
Dronabinol
Protein Kinases
mTOR protein, mouse
Ribosomal Protein S6 Kinases, 70-kDa
TOR Serine-Threonine Kinases
Sirolimus