Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Neuroscience volume 12, pages 1152–1158 (2009)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Kano, M., Ohno-Shosaku, T., Hashimotodani, Y., Uchigashima, M. & Watanabe, M. Endocannabinoid-mediated control of synaptic transmission. Physiol. Rev. 89, 309–380 (2009).

    Article  CAS  Google Scholar 

  2. Wise, L.E., Thorpe, A.J. & Lichtman, A.H. Hippocampal CB(1) receptors mediate the memory impairing effects of delta(9)-tetrahydrocannabinol. Neuropsychopharmacology published online, doi:10.1038/npp.2009.31 (25 March 2009).

    Article  CAS  Google Scholar 

  3. Clarke, J.R. et al. Posttraining activation of CB1 cannabinoid receptors in the CA1 region of the dorsal hippocampus impairs object recognition long-term memory. Neurobiol. Learn. Mem. 90, 374–381 (2008).

    Article  CAS  Google Scholar 

  4. Katona, I. et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J. Neurosci. 19, 4544–4558 (1999).

    Article  CAS  Google Scholar 

  5. Katona, I. et al. Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J. Neurosci. 21, 9506–9518 (2001).

    Article  CAS  Google Scholar 

  6. Katona, I. et al. Molecular composition of the endocannabinoid system at glutamatergic synapses. J. Neurosci. 26, 5628–5637 (2006).

    Article  CAS  Google Scholar 

  7. Kawamura, Y. et al. The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. Neuroscience 26, 2991–3001 (2006).

    Article  CAS  Google Scholar 

  8. Monory, K. et al. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51, 455–466 (2006).

    Article  CAS  Google Scholar 

  9. Takahashi, K.A. & Castillo, P.E. The CB1 cannabinoid receptor mediates glutamatergic synaptic suppression in the hippocampus. Neuroscience 139, 795–802 (2006).

    Article  CAS  Google Scholar 

  10. Derkinderen, P. et al. Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus. J. Neurosci. 23, 2371–2382 (2003).

    Article  CAS  Google Scholar 

  11. Rubino, T., Forlani, G., Viganò, D., Zippel, R. & Parolaro, D. Modulation of extracellular signal-regulated kinases cascade by chronic delta 9-tetrahydrocannabinol treatment. Mol. Cell. Neurosci. 25, 355–362 (2004).

    Article  CAS  Google Scholar 

  12. Ozaita, A., Puighermanal, E. & Maldonado, R. Regulation of PI3K/Akt/GSK-3 pathway by cannabinoids in the brain. J. Neurochem. 102, 1105–1114 (2007).

    Article  CAS  Google Scholar 

  13. Manning, B.D. & Cantley, L.C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).

    Article  CAS  Google Scholar 

  14. Sekulić, A. et al. A direct linkage between the phosphoinositide 3 kinase–AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 60, 3504–3513 (2000).

    PubMed  Google Scholar 

  15. Swiech, L., Perycz, M., Malik, A. & Jaworski, J. Role of mTOR in physiology and pathology of the nervous system. Biochim. Biophys. Acta 1784, 116–132 (2008).

    Article  CAS  Google Scholar 

  16. Jaworski, J. & Sheng, M. The growing role of mTOR in neuronal development and plasticity. Mol. Neurobiol. 34, 205–219 (2006).

    Article  CAS  Google Scholar 

  17. Costa-Mattioli, M., Sossin, W.S., Klann, E. & Sonenberg, N. Translational control of long-lasting synaptic plasticity and memory. Neuron 61, 10–26 (2009).

    Article  CAS  Google Scholar 

  18. Richter, J.D. & Klann, E. Making synaptic plasticity and memory last: mechanisms of translational regulation. Genes Dev. 23, 1–11 (2009).

    Article  CAS  Google Scholar 

  19. Jefferies, H.B. et al. Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k. EMBO J. 16, 3693–3704 (1997).

    Article  CAS  Google Scholar 

  20. Lehman, J.A., Calvo, V. & Gomez-Cambronero, J. Mechanism of ribosomal p70S6 kinase activation by granulocyte macrophage colony-stimulating factor in neutrophils: cooperation of a MEK-related, THR421/SER424 kinase and a rapamycin-sensitive, m-TOR–related THR389 kinase. J. Biol. Chem. 278, 28130–28138 (2003).

    Article  CAS  Google Scholar 

  21. Meyuhas, O. Physiological roles of ribosomal protein S6: one of its kind. Int. Rev. Cell Mol. Biol. 268, 1–37 (2008).

    Article  CAS  Google Scholar 

  22. Ferrari, S. & Thomas, G. S6 phosphorylation and the p70s6k/p85s6k. Crit. Rev. Biochem. Mol. Biol. 29, 385–413 (1994).

    Article  CAS  Google Scholar 

  23. Banko, J.L. et al. The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. J. Neurosci. 25, 9581–9590 (2005).

    Article  CAS  Google Scholar 

  24. Duncan, R.F., Peterson, H., Hagedorn, C.H. & Sevanian, A. Oxidative stress increases eukaryotic initiation factor 4E phosphorylation in vascular cells. Biochem. J. 369, 213–225 (2003).

    Article  CAS  Google Scholar 

  25. Ehninger, D. et al. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat. Med. 14, 843–848 (2008).

    Article  CAS  Google Scholar 

  26. Broadbent, N.J., Squire, L.R. & Clark, R.E. Spatial memory, recognition memory and the hippocampus. Proc. Natl. Acad. Sci. USA 101, 14515–14520 (2004).

    Article  CAS  Google Scholar 

  27. Piomelli, D. et al. Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev. 12, 21–38 (2006).

    Article  CAS  Google Scholar 

  28. Kelleher, R.J. III, Govindarajan, A. & Tonegawa, S. Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44, 59–73 (2004).

    Article  CAS  Google Scholar 

  29. Banko, J.L. & Klann, E. Cap-dependent translation initiation and memory. Prog. Brain Res. 169, 59–80 (2008).

    Article  CAS  Google Scholar 

  30. Bolduc, F.V., Bell, K., Cox, H., Broadie, K.S. & Tully, T. Excess protein synthesis in Drosophila fragile X mutants impairs long-term memory. Nat. Neurosci. 11, 1143–1145 (2008).

    Article  CAS  Google Scholar 

  31. Kandel, E.R. Rapid increase in clusters of presynaptic proteins at onset of long-lasting potentiation. Science 294, 1030–1038 (2001).

    Article  CAS  Google Scholar 

  32. Straiker, A. & Mackie, K. Cannabinoids, electrophysiology and retrograde messengers: challenges for the next 5 years. AAPS J. 8, E272–E276 (2006).

    Article  CAS  Google Scholar 

  33. Elroy-Stein, O. et al. in Translational Control in Biology and Medicine, Translation Initiation via Cellular Internal Ribosome Entry Sites (ed. Mathews, M.B.) (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2008).

  34. Gingras, A.C., Raught, B. & Sonenberg, N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu. Rev. Biochem. 68, 913–963 (1999).

    Article  CAS  Google Scholar 

  35. Wang, X. et al. Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase–dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. Mol. Cell. Biol. 27, 7405–7413 (2007).

    Article  CAS  Google Scholar 

  36. Carracedo, A. et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J. Clin. Invest. 118, 3065–3074 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Blundell, J., Kouser, M. & Powell, C.M. Systemic inhibition of mammalian target of rapamycin inhibits fear memory reconsolidation. Neurobiol. Learn. Mem. 90, 28–35 (2008).

    Article  CAS  Google Scholar 

  38. Page, G. et al. Group I metabotropic glutamate receptors activate the p70S6 kinase via both mammalian target of rapamycin (mTOR) and extracellular signal–regulated kinase (ERK 1/2) signaling pathways in rat striatal and hippocampal synaptoneurosomes. Neurochem. Int. 49, 413–421 (2006).

    Article  CAS  Google Scholar 

  39. Tsokas, P., Ma, T., Iyengar, R., Landau, E.M. & Blitzer, R.D. Mitogen-activated protein kinase upregulates the dendritic translation machinery in long-term potentiation by controlling the mammalian target of rapamycin pathway. J. Neurosci. 27, 5885–5894 (2007).

    Article  CAS  Google Scholar 

  40. Gelinas, J.N. et al. ERK and mTOR signaling couple beta-adrenergic receptors to translation initiation machinery to gate induction of protein synthesis–dependent long-term potentiation. J. Biol. Chem. 282, 27527–27535 (2007).

    Article  CAS  Google Scholar 

  41. Pearson, R.B. & Thomas, G. Regulation of p70s6k/p85s6k and its role in the cell cycle. Prog. Cell Cycle Res. 1, 21–32 (1995).

    Article  CAS  Google Scholar 

  42. Kelleher, R.J. III & Bear, M.F. The autistic neuron: troubled translation? Cell 135, 401–406 (2008).

    Article  CAS  Google Scholar 

  43. Wilson, R.I. & Nicoll, R.A. Endogenous cannabinoids mediate retrograde signaling at hippocampal synapses. Nature 410, 588–592 (2001).

    Article  CAS  Google Scholar 

  44. Kim, M.H. et al. Enhanced NMDA receptor-mediated synaptic transmission, enhanced long-term potentiation, and impaired learning and memory in mice lacking IRSp53. J. Neurosci. 29, 1586–1595 (2009).

    Article  CAS  Google Scholar 

  45. Ohno-Shosaku, T. et al. Presynaptic cannabinoid sensitivity is a major determinant of depolarization-induced retrograde suppression at hippocampal synapses. J. Neurosci. 22, 3864–3872 (2002).

    Article  CAS  Google Scholar 

  46. Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).

    Article  CAS  Google Scholar 

  47. Varvel, S.A., Anum, E.A. & Lichtman, A.H. Disruption of CB(1) receptor signaling impairs extinction of spatial memory in mice. Psychopharmacology (Berl.) 179, 863–872 (2005).

    Article  CAS  Google Scholar 

  48. Zimmer, A., Zimmer, A.M., Hohmann, A.G., Herkenham, M. & Bonner, T.I. Increased mortality, hypoactivity and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. USA 96, 5780–5785 (1999).

    Article  CAS  Google Scholar 

  49. Valjent, E. et al. Involvement of the extracellular signal–regulated kinase cascade for cocaine-rewarding properties. J. Neurosci. 20, 8701–8709 (2000).

    Article  CAS  Google Scholar 

  50. Phillips, R.G. & LeDoux, J.E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285 (1992).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

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

    Emma Puighermanal, Arnau Busquets-Garcia, Rafael Maldonado & Andrés Ozaita

  2. INSERM U862, NeuroCentre Magendie Endocannabinoids and Neuroadaptation Group, University of Bordeaux, Bordeaux, France

    Giovanni Marsicano

  3. Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Mainz, Germany

    Beat Lutz

Authors
  1. Emma Puighermanal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giovanni Marsicano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arnau Busquets-Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Beat Lutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rafael Maldonado
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrés Ozaita
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Andrés Ozaita.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 (PDF 1042 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2369

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing