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:

Reduction in endocannabinoid tone is a homeostatic mechanism for specific inhibitory synapses

Abstract

When chronic alterations in neuronal activity occur, network gain is maintained by global homeostatic scaling of synaptic strength, but the stability of microcircuits can be controlled by unique adaptations that differ from the global changes. It is not understood how specificity of synaptic tuning is achieved. We found that, although a large population of inhibitory synapses was homeostatically scaled down after chronic inactivity, decreased endocannabinoid tone specifically strengthened a subset of GABAergic synapses that express cannabinoid receptors. In rat hippocampal slice cultures, a 3–5-d blockade of neuronal firing facilitated uptake and degradation of anandamide. The consequent reduction in basal stimulation of cannabinoid receptors augmented GABA release probability, fostering rapid depression of synaptic inhibition and on-demand disinhibition. This regulatory mechanism, mediated by activity-dependent changes in tonic endocannabinoid level, permits selective local tuning of inhibitory synapses in hippocampal networks.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Homeostatic downregulation of inhibitory synapses caused by chronic TTX treatment.
Figure 2: Inactivity-induced upregulation of synaptic properties in a subset of inhibitory interneurons.
Figure 3: Tonic activation of CB1R is reduced by activity deprivation.
Figure 4: Chronic inactivity does not alter the responsiveness of CB1R to WIN55212-2, a CB1R agonist.
Figure 5: Basal [Ca2+]in and Ca2+-dependent 2-AG release are not affected by chronic TTX.
Figure 6: Uptake and degradation of basal endocannabinoid are enhanced by activity deprivation.
Figure 7: Deafferentation of CA1 decreases tonic CB1R activity and increases basal GABAergic Pr, mimicking chronic TTX treatment.
Figure 8: Chronic TTX enhances Pr of excitatory synapses independently of tonic endocannabinoid action.

Similar content being viewed by others

References

  1. Turrigiano, G.G. The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135, 422–435 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Houweling, A.R., Bazhenov, M., Timofeev, I., Steriade, M. & Sejnowski, T.J. Homeostatic synaptic plasticity can explain post-traumatic epileptogenesis in chronically isolated neocortex. Cereb. Cortex 15, 834–845 (2005).

    Article  PubMed  Google Scholar 

  3. Trasande, C.A. & Ramirez, J.M. Activity deprivation leads to seizures in hippocampal slice cultures: is epilepsy the consequence of homeostatic plasticity? J. Clin. Neurophysiol. 24, 154–164 (2007).

    Article  PubMed  Google Scholar 

  4. Kim, J. & Tsien, R.W. Synapse-specific adaptations to inactivity in hippocampal circuits achieve homeostatic gain control while dampening network reverberation. Neuron 58, 925–937 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Bausch, S.B., He, S., Petrova, Y., Wang, X.M. & McNamara, J.O. Plasticity of both excitatory and inhibitory synapses is associated with seizures induced by removal of chronic blockade of activity in cultured hippocampus. J. Neurophysiol. 96, 2151–2167 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Buckby, L.E., Jensen, T.P., Smith, P.J. & Empson, R.M. Network stability through homeostatic scaling of excitatory and inhibitory synapses following inactivity in CA3 of rat organotypic hippocampal slice cultures. Mol. Cell. Neurosci. 31, 805–816 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Echegoyen, J., Neu, A., Graber, K.D. & Soltesz, I. Homeostatic plasticity studied using in vivo hippocampal activity-blockade: synaptic scaling, intrinsic plasticity and age-dependence. PLoS One 2, e700 (2007).

    Article  PubMed  Google Scholar 

  8. Burrone, J. & Murthy, V.N. Synaptic gain control and homeostasis. Curr. Opin. Neurobiol. 13, 560–567 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Alger, B.E. Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog. Neurobiol. 68, 247–286 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. 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  PubMed  Google Scholar 

  11. 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  PubMed  Google Scholar 

  12. Marsicano, G. & Lutz, B. Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur. J. Neurosci. 11, 4213–4225 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Chen, K. et al. Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures. Neuron 39, 599–611 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Falenski, K.W., Blair, R.E., Sim-Selley, L.J., Martin, B.R. & DeLorenzo, R.J. Status epilepticus causes a long-lasting redistribution of hippocampal cannabinoid type 1 receptor expression and function in the rat pilocarpine model of acquired epilepsy. Neuroscience 146, 1232–1244 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Rinaldi-Carmona, M. et al. Modulation of CB1 cannabinoid receptor functions after a long-term exposure to agonist or inverse agonist in the Chinese hamster ovary cell expression system. J. Pharmacol. Exp. Ther. 287, 1038–1047 (1998).

    CAS  PubMed  Google Scholar 

  16. Hsieh, C., Brown, S., Derleth, C. & Mackie, K. Internalization and recycling of the CB1 cannabinoid receptor. J. Neurochem. 73, 493–501 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Hartman, K.N., Pal, S.K., Burrone, J. & Murthy, V.N. Activity-dependent regulation of inhibitory synaptic transmission in hippocampal neurons. Nat. Neurosci. 9, 642–649 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Kilman, V., van Rossum, M.C. & Turrigiano, G.G. Activity deprivation reduces miniature IPSC amplitude by decreasing the number of postsynaptic GABAA receptors clustered at neocortical synapses. J. Neurosci. 22, 1328–1337 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Turrigiano, G.G., Leslie, K.R., Desai, N.S., Rutherford, L.C. & Nelson, S.B. Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391, 892–896 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Bertrand, S. & Lacaille, J.C. Unitary synaptic currents between lacunosum-moleculare interneurones and pyramidal cells in rat hippocampus. J. Physiol. (Lond.) 532, 369–384 (2001).

    Article  CAS  Google Scholar 

  21. Bartley, A.F., Huang, Z.J., Huber, K.M. & Gibson, J.R. Differential activity-dependent, homeostatic plasticity of two neocortical inhibitory circuits. J. Neurophysiol. 100, 1983–1994 (2008).

    Article  PubMed  Google Scholar 

  22. Maffei, A., Nelson, S.B. & Turrigiano, G.G. Selective reconfiguration of layer 4 visual cortical circuitry by visual deprivation. Nat. Neurosci. 7, 1353–1359 (2004).

    Article  CAS  Google Scholar 

  23. Poncer, J.C., McKinney, R.A., Gahwiler, B.H. & Thompson, S.M. Either N- or P-type calcium channels mediate GABA release at distinct hippocampal inhibitory synapses. Neuron 18, 463–472 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Wilson, R.I., Kunos, G. & Nicoll, R.A. Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31, 453–462 (2001).

    Article  CAS  Google Scholar 

  25. Neu, A., Foldy, C. & Soltesz, I. Postsynaptic origin of CB1-dependent tonic inhibition of GABA release at cholecystokinin-positive basket cell to pyramidal cell synapses in the CA1 region of the rat hippocampus. J. Physiol. (Lond.) 578, 233–247 (2007).

    Article  CAS  Google Scholar 

  26. Faber, D.S. & Korn, H. Applicability of the coefficient of variation method for analyzing synaptic plasticity. Biophys. J. 60, 1288–1294 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Kim, J. & Alger, B.E. Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus. Nat. Neurosci. 7, 697–698 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Makara, J.K. et al. Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus. Nat. Neurosci. 8, 1139–1141 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Fortin, D.A., Trettel, J. & Levine, E.S. Brief trains of action potentials enhance pyramidal neuron excitability via endocannabinoid-mediated suppression of inhibition. J. Neurophysiol. 92, 2105–2112 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Giuffrida, A., Beltramo, M. & Piomelli, D. Mechanisms of endocannabinoid inactivation: biochemistry and pharmacology. J. Pharmacol. Exp. Ther. 298, 7–14 (2001).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. Chevaleyre, V. & Castillo, P.E. Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability. Neuron 38, 461–472 (2003).

    Article  CAS  Google Scholar 

  34. Varvel, S.A., Wise, L.E., Niyuhire, F., Cravatt, B.F. & Lichtman, A.H. Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. Neuropsychopharmacology 32, 1032–1041 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Okamoto, Y., Wang, J., Morishita, J. & Ueda, N. Biosynthetic pathways of the endocannabinoid anandamide. Chem. Biodivers. 4, 1842–1857 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Nyilas, R. et al. Enzymatic machinery for endocannabinoid biosynthesis associated with calcium stores in glutamatergic axon terminals. J. Neurosci. 28, 1058–1063 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Egertová, M., Simon, G.M., Cravatt, B.F. & Elphick, M.R. Localization of N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) expression in mouse brain: A new perspective on N-acylethanolamines as neural signaling molecules. J. Comp. Neurol. 506, 604–615 (2008).

    Article  PubMed  Google Scholar 

  38. Cristino, L. et al. Immunohistochemical localization of anabolic and catabolic enzymes for anandamide and other putative endovanilloids in the hippocampus and cerebellar cortex of the mouse brain. Neuroscience 151, 955–968 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Leung, D., Saghatelian, A., Simon, G.M. & Cravatt, B.F. Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry 45, 4720–4726 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Luk, T. et al. Identification of a potent and highly efficacious, yet slowly desensitizing CB1 cannabinoid receptor agonist. Br. J. Pharmacol. 142, 495–500 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Sugiura, T. Physiological roles of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Biofactors 35, 88–97 (2009).

    Article  PubMed  Google Scholar 

  42. Kim, J., Isokawa, M., Ledent, C. & Alger, B.E. Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus. J. Neurosci. 22, 10182–10191 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Losonczy, A., Biro, A.A. & Nusser, Z. Persistently active cannabinoid receptors mute a subpopulation of hippocampal interneurons. Proc. Natl. Acad. Sci. USA 101, 1362–1367 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Hashimotodani, Y., Ohno-Shosaku, T. & Kano, M. Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus. J. Neurosci. 27, 1211–1219 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Morozov, Y.M., Ben-Ari, Y. & Freund, T.F. The spatial and temporal pattern of fatty acid amide hydrolase expression in rat hippocampus during postnatal development. Eur. J. Neurosci. 20, 459–466 (2004).

    Article  PubMed  Google Scholar 

  46. Fernández-Ruiz, J., Berrendero, F., Hernandez, M.L. & Ramos, J.A. The endogenous cannabinoid system and brain development. Trends Neurosci. 23, 14–20 (2000).

    Article  PubMed  Google Scholar 

  47. Földy, C., Neu, A., Jones, M.V. & Soltesz, I. Presynaptic, activity-dependent modulation of cannabinoid type 1 receptor–mediated inhibition of GABA release. J. Neurosci. 26, 1465–1469 (2006).

    Article  Google Scholar 

  48. Glickfeld, L.L. & Scanziani, M. Distinct timing in the activity of cannabinoid-sensitive and cannabinoid-insensitive basket cells. Nat. Neurosci. 9, 807–815 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. McKinney, R.A., Debanne, D., Gahwiler, B.H. & Thompson, S.M. Lesion-induced axonal sprouting and hyperexcitability in the hippocampus in vitro: implications for the genesis of post-traumatic epilepsy. Nat. Med. 3, 990–996 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. van der Stelt, M. & Di Marzo, V. Cannabinoid receptors and their role in neuroprotection. Neuromolecular Med. 7, 37–50 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank T. Abrams and the members of the Alger laboratory for helpful comments and suggestions on this work. We thank T. Gover for expert assistance with the calcium-imaging experiments. This research was supported by US Institutes of Health grants R01 DA014625 and R01 MH077277 to B.E.A.

Author information

Authors and Affiliations

Authors

Contributions

J.K. and B.E.A. designed the research and wrote the manuscript. J.K. conducted the experiments.

Corresponding author

Correspondence to Bradley E Alger.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 430 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, J., Alger, B. Reduction in endocannabinoid tone is a homeostatic mechanism for specific inhibitory synapses. Nat Neurosci 13, 592–600 (2010). https://doi.org/10.1038/nn.2517

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2517

This article is cited by

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