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TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus

Nature Neuroscience volume 13, pages 1511–1518 (2010)Cite this article

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Abstract

The transient receptor potential TRPV1 is a nonselective cation channel that mediates pain sensations and is commonly activated by a wide variety of exogenous and endogenous, physical and chemical stimuli. Although TRPV1 receptors are mainly found in nociceptive neurons of the peripheral nervous system, these receptors have also been found in the brain, where their role is far less understood. Activation of TRPV1 reportedly regulates neurotransmitter release at several central synapses. However, we found that TRPV1 suppressed excitatory transmission in rat and mouse dentate gyrus by regulating postsynaptic function in an input-specific manner. This suppression was a result of Ca2+-calcineurin and clathrin-dependent internalization of AMPA receptors. Moreover, synaptic activation of TRPV1 triggered a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamide in a type 1 cannabinoid receptor–independent manner. Thus, our findings reveal a previously unknown form of endocannabinoid- and TRPV1-mediated regulation of synaptic strength at central synapses.

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Figure 1: Functional evidence for TRPV1 receptors in the dentate gyrus.
Figure 2: Postsynaptic TRPV1-mediated suppression of excitatory transmission.
Figure 3: TRPV1-mediated long-term depression at MPP-DGC synapses.
Figure 4: Role of TRPV1 receptors in long-term potentiation at MPP-DGC synapses.
Figure 5: Activation of mGluR5 is necessary, but not sufficient, to induce TRPV1-LTD.
Figure 6: Molecular mechanism underlying TRPV1-mediated depression of synaptic transmission.
Figure 7: The endocannabinoid AEA suppresses excitatory synaptic transmission via TRPV1 receptors.
Figure 8: Anandamide mediates TRPV1-LTD in the dentate gyrus.

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References

  1. Caterina, M.J. & Julius, D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. 24, 487–517 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Ramsey, I.S., Delling, M. & Clapham, D.E. An introduction to TRP channels. Annu. Rev. Physiol. 68, 619–647 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Ross, R.A. Anandamide and vanilloid TRPV1 receptors. Br. J. Pharmacol. 140, 790–801 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Caterina, M.J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Kauer, J.A. & Gibson, H.E. Hot flash: TRPV channels in the brain. Trends Neurosci. 32, 215–224 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Cristino, L. et al. Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience 139, 1405–1415 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Sanchez, J.F., Krause, J.E. & Cortright, D.N. The distribution and regulation of vanilloid receptor VR1 and VR1 5′ splice variant RNA expression in rat. Neuroscience 107, 373–381 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Táth, A. et al. Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain. Brain Res. Mol. Brain Res. 135, 162–168 (2005).

    Article  Google Scholar 

  9. Sasamura, T., Sasaki, M., Tohda, C. & Kuraishi, Y. Existence of capsaicin-sensitive glutamatergic terminals in rat hypothalamus. Neuroreport 9, 2045–2048 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Mezey, E. et al. Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc. Natl. Acad. Sci. USA 97, 3655–3660 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Roberts, J.C., Davis, J.B. & Benham, C.D. [3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution. Brain Res. 995, 176–183 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Yang, K., Kumamoto, E., Furue, H. & Yoshimura, M. Capsaicin facilitates excitatory but not inhibitory synaptic transmission in substantia gelatinosa of the rat spinal cord. Neurosci. Lett. 255, 135–138 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Doyle, M.W., Bailey, T.W., Jin, Y.H. & Andresen, M.C. Vanilloid receptors presynaptically modulate cranial visceral afferent synaptic transmission in nucleus tractus solitarius. J. Neurosci. 22, 8222–8229 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Marinelli, S. et al. Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors. J. Neurosci. 23, 3136–3144 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Marinelli, S., Vaughan, C.W., Christie, M.J. & Connor, M. Capsaicin activation of glutamatergic synaptic transmission in the rat locus coeruleus in vitro. J. Physiol. (Lond.) 543, 531–540 (2002).

    Article  CAS  Google Scholar 

  16. Musella, A. et al. TRPV1 channels facilitate glutamate transmission in the striatum. Mol. Cell. Neurosci. 40, 89–97 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Gibson, H.E., Edwards, J.G., Page, R.S., Van Hook, M.J. & Kauer, J.A. TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons. Neuron 57, 746–759 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Maione, S. et al. TRPV1 channels control synaptic plasticity in the developing superior colliculus. J. Physiol. (Lond.) 587, 2521–2535 (2009).

    Article  CAS  Google Scholar 

  19. 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 

  20. Maccarrone, M. et al. Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum. Nat. Neurosci. 11, 152–159 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Marsch, R. et al. Reduced anxiety, conditioned fear and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J. Neurosci. 27, 832–839 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li, H.B. et al. Antistress effect of TRPV1 channel on synaptic plasticity and spatial memory. Biol. Psychiatry 64, 286–292 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Benninger, F., Freund, T.F. & Hajos, N. Control of excitatory synaptic transmission by capsaicin is unaltered in TRPV1 vanilloid receptor knockout mice. Neurochem. Int. 52, 89–94 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Errington, M.L., Lynch, M.A. & Bliss, T.V. Long-term potentiation in the dentate gyrus: induction and increased glutamate release are blocked by D(-)aminophosphonovalerate. Neuroscience 20, 279–284 (1987).

    Article  CAS  PubMed  Google Scholar 

  25. Fagni, L., Chavis, P., Ango, F. & Bockaert, J. Complex interactions between mGluRs, intracellular Ca2+ stores and ion channels in neurons. Trends Neurosci. 23, 80–88 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Mulkey, R.M., Endo, S., Shenolikar, S. & Malenka, R.C. Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 369, 486–488 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Winder, D.G. & Sweatt, J.D. Roles of serine/threonine phosphatases in hippocampal synaptic plasticity. Nat. Rev. Neurosci. 2, 461–474 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Lai, M.M. et al. The calcineurin-dynamin 1 complex as a calcium sensor for synaptic vesicle endocytosis. J. Biol. Chem. 274, 25963–25966 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Carroll, R.C. et al. Dynamin-dependent endocytosis of ionotropic glutamate receptors. Proc. Natl. Acad. Sci. USA 96, 14112–14117 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Smart, D. et al. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br. J. Pharmacol. 129, 227–230 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. van der Stelt, M. et al. Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels. EMBO J. 24, 3026–3037 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zygmunt, P.M. et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. Piomelli, D. The molecular logic of endocannabinoid signaling. Nat. Rev. Neurosci. 4, 873–884 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Golech, S.A. et al. Human brain endothelium: coexpression and function of vanilloid and endocannabinoid receptors. Brain Res. Mol. Brain Res. 132, 87–92 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. 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  PubMed  Google Scholar 

  37. Chevaleyre, V., Takahashi, K.A. & Castillo, P.E. Endocannabinoid-mediated synaptic plasticity in the CNS. Annu. Rev. Neurosci. 29, 37–76 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. 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 

  39. Regehr, W.G., Carey, M.R. & Best, A.R. Activity-dependent regulation of synapses by retrograde messengers. Neuron 63, 154–170 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bacci, A., Huguenard, J.R. & Prince, D.A. Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids. Nature 431, 312–316 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Grueter, B.A., Brasnjo, G. & Malenka, R.C. Postsynaptic TRPV1 triggers cell type–specific long-term depression in the nucleus accumbens. Nat. Neurosci. advance online publication, doi:10.1038/nn.2685 (14 November 2010).

  42. Chiu, C.Q. & Castillo, P.E. Input-specific plasticity at excitatory synapses mediated by endocannabinoids in the dentate gyrus. Neuropharmacology 54, 68–78 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Starowicz, K., Nigam, S. & Di Marzo, V. Biochemistry and pharmacology of endovanilloids. Pharmacol. Ther. 114, 13–33 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Kim, J. & Alger, B.E. Reduction in endocannabinoid tone is a homeostatic mechanism for specific inhibitory synapses. Nat. Neurosci. 13, 592–600 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pingle, S.C., Matta, J.A. & Ahern, G.P. Capsaicin receptor: TRPV1 a promiscuous TRP channel. Handb. Exp. Pharmacol. 179, 155–171 (2007).

    Article  CAS  Google Scholar 

  46. Tominaga, M. et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21, 531–543 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Hu, H.J., Bhave, G. & Gereau, R.W. IV. Prostaglandin and protein kinase A–dependent modulation of vanilloid receptor function by metabotropic glutamate receptor 5: potential mechanism for thermal hyperalgesia. J. Neurosci. 22, 7444–7452 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kim, Y.H. et al. Membrane-delimited coupling of TRPV1 and mGluR5 on presynaptic terminals of nociceptive neurons. J. Neurosci. 29, 10000–10009 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wong, G.Y. & Gavva, N.R. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: recent advances and setbacks. Brain Res. Rev. 60, 267–277 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Marsden, K.C., Beattie, J.B., Friedenthal, J. & Carroll, R.C. NMDA receptor activation potentiates inhibitory transmission through GABA receptor–associated protein-dependent exocytosis of GABA(A) receptors. J. Neurosci. 27, 14326–14337 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all members of the Castillo laboratory for comments on the manuscript, B. Connors and S. Nawy for kindly providing Trpv1−/− mice, and R. Carroll and A. Rodenas-Ruano for providing DGC cultures. This work was supported by US National Institutes of Health grants to P.E.C. (DA017392, MH081935). A.E.C. was partially supported by a Ruth L. Kirschstein Award (F32 NS071821).

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  1. Department of Neuroscience, Dominick P. Purpura, Albert Einstein College of Medicine, New York, New York, USA

    Andrés E Chávez, Chiayu Q Chiu & Pablo E Castillo

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A.E.C. and C.Q.C. performed all of the experiments and analyzed the results. A.E.C., C.Q.C. and P.E.C. designed the experiments, interpreted the results and wrote the paper.

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Correspondence to Pablo E Castillo.

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Chávez, A., Chiu, C. & Castillo, P. TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. Nat Neurosci 13, 1511–1518 (2010). https://doi.org/10.1038/nn.2684

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