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:

Postsynaptic endocannabinoid release is critical to long-term depression in the striatum

Nature Neuroscience volume 5, pages 446–451 (2002)Cite this article

Abstract

The striatum functions critically in movement control and habit formation. The development and function of cortical input to the striatum are thought to be regulated by activity-dependent plasticity of corticostriatal glutamatergic synapses. Here we show that the induction of a form of striatal synaptic plasticity, long-term depression (LTD), is dependent on activation of the CB1 cannabinoid receptor. LTD was facilitated by blocking cellular endocannabinoid uptake, and postsynaptic loading of anandamide (AEA) produced presynaptic depression. The endocannabinoid necessary for striatal LTD is thus likely to be released postsynaptically as a retrograde messenger. These findings demonstrate a new role for endocannabinoids in the induction of long-term synaptic plasticity in a circuit necessary for habit formation and motor control.

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: Striatal LTD was not seen in CB1−/− mice.
Figure 2: CB1−/− mice showed a loss of presynaptic cannabinoid effects in striatum.
Figure 3: Induction of striatal LTD depended on CB1 receptor activation.
Figure 4: Blocking uptake of endocannabinoids rescued LTD induction in cells filled with 10 mM EGTA.
Figure 5: Intracellular postsynaptic application of AEA resulted in synaptic depression.

Similar content being viewed by others

References

  1. Wilson, C. J. & Kawaguchi, Y. The origins of two-state spontaneous membrane potential fluctuations of neostriatal spiny neurons. J. Neurosci. 16, 2397–2410 (1996).

    Article  CAS  Google Scholar 

  2. Calabresi, P., Pisani, A., Mercuri, N. B. & Bernardi, G. The corticostriatal projection: from synaptic plasticity to dysfunctions of the basal ganglia. Trends Neurosci. 19, 19–24 (1996).

    Article  CAS  Google Scholar 

  3. Calabresi, P., Maj, R., Pisani, A., Mercuri, N. B. & Bernardi, G. Long-term synaptic depression in the striatum: physiological and pharmacological characterization. J. Neurosci. 12, 4224–4233 (1992).

    Article  CAS  Google Scholar 

  4. Lovinger, D. M., Tyler, E. C. & Merritt, A. Short- and long-term synaptic depression in rat neostriatum. J. Neurophysiol. 70, 1937–1949 (1993).

    Article  CAS  Google Scholar 

  5. Walsh, J. P. Depression of excitatory synaptic input in rat striatal neurons. Brain Res. 608, 123–128 (1993).

    Article  CAS  Google Scholar 

  6. Tang, K., Low, M. J., Grandy, D. K. & Lovinger, D. M. Dopamine-dependent synaptic plasticity in striatum during in vivo development. Proc. Natl. Acad. Sci. USA 98, 1255–1260 (2001).

    Article  CAS  Google Scholar 

  7. Knowlton, B. J., Mangels, J. A. & Squire, L. R. A neostriatal habit learning system in humans. Science 273, 1399–1402 (1996).

    Article  CAS  Google Scholar 

  8. Jog, M. S., Kubota, Y., Connolly, C. I., Hillegaart, V. & Graybiel, A. M. Building neural representations of habits. Science 286, 1745–1749 (1999).

    Article  CAS  Google Scholar 

  9. Graybiel, A. M. & Rauch, S. L. Toward a neurobiology of obsessive–compulsive disorder. Neuron 28, 343–347 (2000).

    Article  CAS  Google Scholar 

  10. Leckman, J. F. & Riddle, M. A. Tourette's syndrome: when habit-forming systems form habits of their own? Neuron 28, 349–354 (2000).

    Article  CAS  Google Scholar 

  11. Berke, J. D. & Hyman, S. E. Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25, 515–532 (2000).

    Article  CAS  Google Scholar 

  12. Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C. & Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564 (1990).

    Article  CAS  Google Scholar 

  13. Devane, W. A., Dysarz, F. A. 3rd, Johnson, M. R., Melvin, L. S. & Howlett, A. C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34, 605–613 (1988).

    CAS  PubMed  Google Scholar 

  14. Di Marzo, V., Melck, D., Bisogno, T. & De Petrocellis, L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 21, 521–528 (1998).

    Article  CAS  Google Scholar 

  15. Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).

    Article  CAS  Google Scholar 

  16. Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83–90 (1995).

    Article  CAS  Google Scholar 

  17. Sugiura, T. et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89–97 (1995).

    Article  CAS  Google Scholar 

  18. Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773–778 (1997).

    Article  CAS  Google Scholar 

  19. Herkenham, M., Lynn, A. B., de Costa, B. R. & Richfield, E. K. Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res. 547, 267–274 (1991).

    Article  CAS  Google Scholar 

  20. Rodriguez, J. J., Mackie, K. & Pickel, V. M. Ultrastructural localization of the CB1 cannabinoid receptor in μ-opioid receptor patches of the rat caudate putamen nucleus. J. Neurosci. 21, 823–833 (2001).

    Article  CAS  Google Scholar 

  21. Gerdeman, G. & Lovinger, D. M. CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J. Neurophysiol. 85, 468–471 (2001).

    Article  CAS  Google Scholar 

  22. Huang, C. C. et al. Presynaptic mechanisms underlying cannabinoid inhibition of excitatory synaptic transmission in rat striatal neurons. J. Physiol. (Lond.) 532, 731–748 (2001).

    Article  CAS  Google Scholar 

  23. Gough, A. L. & Olley, J. E. Catalepsy induced by intrastriatal injections of Δ9-THC and 11-OH-Δ9-THC in the rat. Neuropharmacology 17, 137–144 (1978).

    Article  CAS  Google Scholar 

  24. 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 

  25. Steiner, H., Bonner, T. I., Zimmer, A. M., Kitai, S. T. & Zimmer, A. Altered gene expression in striatal projection neurons in CB1 cannabinoid receptor knockout mice. Proc. Natl. Acad. Sci. USA 96, 5786–5790 (1999).

    Article  CAS  Google Scholar 

  26. Ledent, C. et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283, 401–404 (1999).

    Article  CAS  Google Scholar 

  27. Choi, S. & Lovinger, D. M. Decreased probability of neurotransmitter release underlies striatal long-term depression and postnatal development of corticostriatal synapses. Proc. Natl. Acad. Sci. USA 94, 2665–2670 (1997).

    Article  CAS  Google Scholar 

  28. Choi, S. & Lovinger, D. M. Decreased frequency but not amplitude of quantal synaptic responses associated with expression of corticostriatal long-term depression. J. Neurosci. 17, 8613–8620 (1997).

    Article  CAS  Google Scholar 

  29. Di Marzo, V. et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686–691 (1994).

    Article  CAS  Google Scholar 

  30. Giuffrida, A. et al. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat. Neurosci. 2, 358–363 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Ohno-Shosaku, T., Maejima, T. & Kano, M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29, 729–738 (2001).

    Article  CAS  Google Scholar 

  33. Kreitzer, A. C. & Regehr, W. G. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29, 717–727 (2001).

    Article  CAS  Google Scholar 

  34. Levenes, C., Daniel, H., Soubrie, P. & Crepel, F. Cannabinoids decrease excitatory synaptic transmission and impair long-term depression in rat cerebellar Purkinje cells. J. Physiol. (Lond.) 510, 867–879 (1998).

    Article  CAS  Google Scholar 

  35. Auclair, N., Otani, S., Soubrie, P. & Crepel, F. Cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pyramidal neurons. J. Neurophysiol. 83, 3287–3293 (2000).

    Article  CAS  Google Scholar 

  36. Cadas, H., Gaillet, S., Beltramo, M., Venance, L. & Piomelli, D. Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. J. Neurosci. 16, 3934–3942 (1996).

    Article  CAS  Google Scholar 

  37. Partridge, J. G., Tang, K. C. & Lovinger, D. M. Regional and postnatal heterogeneity of activity-dependent long-term changes in synaptic efficacy in the dorsal striatum. J. Neurophysiol. 84, 1422–1429 (2000).

    Article  CAS  Google Scholar 

  38. Beltramo, M. et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277, 1094–1097 (1997).

    Article  CAS  Google Scholar 

  39. Hillard, C. J. & Jarrahian, A. The movement of N-arachidonoyle-thanolamine (anandamide) across cellular membranes. Chem. Phys. Lipids 108, 123–134 (2000).

    Article  CAS  Google Scholar 

  40. Deutsch, D. G. et al. The cellular uptake of anandamide is coupled to its breakdown by fatty-acid amide hydrolase. J. Biol. Chem. 276, 6967–6973 (2001).

    Article  CAS  Google Scholar 

  41. Day, T. A., Rakhshan, F., Deutsch, D. G. & Barker, E. L. Role of fatty acid amide hydrolase in the transport of the endogenous cannabinoid anandamide. Mol. Pharmacol. 59, 1369–1375 (2001).

    Article  CAS  Google Scholar 

  42. Calabresi, P. et al. Abnormal synaptic plasticity in the striatum of mice lacking dopamine D2 receptors. J. Neurosci. 17, 4536–4544 (1997).

    Article  CAS  Google Scholar 

  43. Gubellini, P. et al. Selective involvement of mGlu1 receptors in corticostriatal LTD. Neuropharmacology 839–846 (2001).

  44. Sung, K.-W., Choi, S. & Lovinger, D.M. (2001) Activation of group I metabotropic glutamate receptors is necessary for induction of long-term synaptic depression at striatal synapses. J. Neurophysiol. 86, 2405–2412 (2001).

    Article  CAS  Google Scholar 

  45. Maejima, T., Hashimoto, K., Yoshida, T., Aiba, A. & Kano, M. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron 31, 463–475 (2001).

    Article  CAS  Google Scholar 

  46. Varma, N., Carlson, G.C., Ledent, C. & Alger, B.E. Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J. Neurosci. 21, RC188 (1–5) (2001).

    Article  Google Scholar 

  47. Calabresi, P. et al. A critical role of the nitric oxide/cGMP pathway in corticostriatal long-term depression. J. Neurosci. 19, 2489–2499 (1999).

    Article  CAS  Google Scholar 

  48. Maccarrone, M. et al. Anandamide uptake by human endothelial cells and its regulation by nitric oxide. J. Biol. Chem. 275, 13484–13492 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank T. Möykkynen for technical assistance, G. Kunos, K. Mackie and D. Winder for helpful comments during manuscript preparation, and A. Zimmer for providing CB1+/− mice. This work was supported by NIH grants NS30470 (D.M.L.) and DA05923 (G.L.G.).

Author information

Author notes

  1. Gregory L. Gerdeman

    Present address: Department of Pharmacology, The University of Arizona Health Sciences Center, Tucson, Arizona, 85724-5050, USA

  2. Jennifer Ronesi & David M. Lovinger

    Present address: Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, 158H Park 5 Building, Rockville, Maryland, 20852, USA

Authors and Affiliations

  1. Departments of Molecular Physiology & Biophysics and Pharmacology, and Center for Molecular Neuroscience, Vanderbilt University, Nashville, 37232-0615, Tennessee, USA

    Gregory L. Gerdeman, Jennifer Ronesi & David M. Lovinger

Authors
  1. Gregory L. Gerdeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer Ronesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David M. Lovinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David M. Lovinger.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gerdeman, G., Ronesi, J. & Lovinger, D. Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci 5, 446–451 (2002). https://doi.org/10.1038/nn832

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn832

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