Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1α
Open accessAbstract
Endocannabinoids (eCBs) have emerged as key activity-dependent signals that, by activating presynaptic cannabinoid receptors (i.e., CB1) coupled to G(i/o) protein, can mediate short-term and long-term synaptic depression (LTD). While the presynaptic mechanisms underlying eCB-dependent short-term depression have been identified, the molecular events linking CB1 receptors to LTD are unknown. Here we show in the hippocampus that long-term, but not short-term, eCB-dependent depression of inhibitory transmission requires presynaptic cAMP/PKA signaling. We further identify the active zone protein RIM1alpha as a key mediator of both CB1 receptor effects on the release machinery and eCB-dependent LTD in the hippocampus. Moreover, we show that eCB-dependent LTD in the amygdala and hippocampus shares major mechanistic features. These findings reveal the signaling pathway by which CB1 receptors mediate long-term effects of eCBs in two crucial brain structures. Furthermore, our results highlight a conserved mechanism of presynaptic plasticity in the brain.
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In vertebrates, RIM1α is required for all types of long-term presynaptic plasticity analyzed.
“In vertebrates, RIM1α is additionally required for all types of long-term presynaptic plasticity analyzed (Castillo et al., 2002; Huang et al., 2005; Chevaleyre et al., 2007; Fourcaudot et al., 2008; Pelkey et al., 2008; Lachamp et al., 2009).”
From The Presynaptic Active Zone (2012) · cites this paper as Chevaleyre et al., 2007
All forms of presynaptic long-term plasticity investigated-both LTP and LTD-are blocked by the constitutive knockout of RIM1α.
“Strikingly, up to now all forms of presynaptic long-term plasticity investigated—both long-term potentiation (LTP) and long-term depression (LTD)—are blocked by the constitutive knockout of RIM1α (which only partly impairs basal release since all other RIM isoforms are still present), suggesting that the amount of RIM1α available at a synapse is crucial (Castillo et al., 2002; Chevaleyre et al., 2”
From The Presynaptic Active Zone (2012) · cites this paper as Chevaleyre et al., 2007
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“…for the cannabinoid signaling system in long term potentiation (Carlson et al., 2002) and long term depression (Chevaleyre & Castillo, 2003, 2004; Chevaleyre et al., 2007; Edwards et al., 2008; Heifets et al., 2008; Nahir et al., 2010) which should also be investigated following the induction of…”
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“Discussion RIM1 is an active zone protein that is essential for presynaptic short- and long-term plasticity (11, 16, 26).”
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Regulation of excitability and plasticity by endocannabinoids and PKA in developing hippocampus
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Phytocannabinoids and endocannabinoids.
Fišar, Z. (2009) · Current Drug Abuse Reviews · doi:10.2174/1874473710902010051 · Cited by 66 · see citing works
Martinez, A. A., Macheda, T., Morgese, M. G., Trabace, L., & Giuffrida, A. (2011) · Neuroscience Research · doi:10.1016/j.neures.2011.12.006 · Cited by 56 · see citing works
“…striatal neurotransmission via a PKA-dependent mechanism affecting the exocytosis of synaptic vesicles (Seino and Shibasaki 2005) and/or endocannabinoid-mediated plasticity at excitatory and inhibitory synapses (Chevaleyre et al. 2007; Heifets et al. 2008; Mato et al. 2008; Pan et al. 2008).”
Huang, Y.-Y., Yasuda, H., Sarihi, A., & Tsumoto, T. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0899-08.2008 · Cited by 64 · see citing works
“The suppressive action of the eCB– CB1R may be ascribable to the decrease in cAMP in presynaptic terminals (Chevaleyre et al., 2007).”
BackgroundRamikie, T. S., & Patel, S. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2011.08.037 · Cited by 62 · see citing works
“These data implicate RIM1α as an important synaptic protein mediating long-term synaptic effects of eCBs in the BLA, and other brain regions such as the hippocampus (Chevaleyre et al., 2007). eCB signaling has also been explored at the circuit level in vitro.”
InfluentialArtinian, J., & Lacaille, J. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.11.012 · Cited by 61 · see citing works
Eleore, L., López-Ramos, J., Guerra-Narbona, R., & Delgado-García, J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023538 · Cited by 61 · see citing works
The readily-releasable pool dynamically regulates multivesicular release.
Vaden, J. H., Banumurthy, G., Gusarevich, E. S., Overstreet-Wadiche, L., & Wadiche, J. I. (2019) · eLife · doi:10.7554/elife.47434 · Cited by 61 · see citing works
“…accompanies the cAMP/PKA-mediated enhancement of coupling between Ca2+ channels and synaptic vesicles (Salin et al., 1996; Chen and Regehr, 1997; Chevaleyre et al., 2007; Pelkey et al., 2008; Ariel et al., 2012; Midorikawa and Sakaba, 2017) because a change in Pr during the first stimulus…”
BackgroundEndocannabinoid dynamics gate spike-timing dependent depression and potentiation
Cui, Y.-H., Prokin, I., Xu, H., Delord, B., Genet, S., Venance, L., & Berry, H. (2016) · eLife · doi:10.7554/elife.13185 · Cited by 60 · see citing works
“In the hippocampus ( Chevaleyre et al, 2007 ) and nucleus accumbens ( Mato et al., 2008 ), the expression of frequency-dependent eCB-LTD is blocked when cAMP levels are increased by the adenylyl-cyclase activator forskolin.”
BackgroundCannabinoid Modulation of the Stressed Hippocampus
Scarante, F. F., Vila-Verde, C., Lopes, V. D., Ferreira‐Junior, N. C., Guimarães, F. S., & Campos, A. C. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00411 · Cited by 64 · see citing works
“This effect is dependent on the cAMP/PKA pathway (Chevaleyre et al., 2007).”
BackgroundPan, B., Zhong, P., Sun, D., & Liu, Q.-S. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.1040-11.2011 · Cited by 59 · see citing works
“A common property for this type of LTD/I-LTD is that CB1 antagonists block the induction of CB1-LTD/I-LTD, but cannot reverse the established LTD/I-LTD when applied after LTD induction (Chevaleyre and Castillo, 2003; Ronesi and Lovinger, 2005; Pan et al., 2008a), suggesting that other downstream signaling mechanisms m…”
BackgroundPelkey, K. A., & McBain, C. J. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2007.148635 · Cited by 58 · see citing works
“In particular, recent years have witnessed a flood of publications describing a critical role for endocannabinoids (eCBs) as retrograde mediators of presynaptic LTD throughout the CNS, and some reports suggest a priviledged role for Ca2+ influx through CP-AMPARs in eCB generation (Gerdeman et al. 2002; Chevaleyre & Ca…”
BackgroundArgyrousi, E. K., Heckman, P. R. A., & Prickaerts, J. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.02.004 · Cited by 64 · see citing works
“Additionally, presynaptic cAMP levels are also regulated by GPCRs independent of CAMKII, including metabotropic glutamate receptors (Schoepp, 2001) and cannabinoid receptors (Alonso et al., 2017; Chevaleyre et al., 2007) (Fig.”
BackgroundRAB GTPases and RAB-interacting proteins and their role in the control of cognitive functions
D’Adamo, P., Masetti, M., Bianchi, V., Morè, L., Mignogna, M. L., Giannandrea, M., & Gatti, S. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.12.009 · Cited by 54 · see citing works
Assortment of GABAergic Plasticity in the Cortical Interneuron Melting Pot
Méndez, P., & Bacci, A. (2011) · Neural Plasticity · doi:10.1155/2011/976856 · Cited by 57 · see citing works
“This form of long-lasting plasticity of GABAergic transmission, termed eCB-dependent long-term depression (eCBLTD), depends on CB1R-mediated regulation of presynaptic protein kinase A (PKA) and the phosphatase calcineurin [117, 118].”
BackgroundCannabinoids Excite Circadian Clock Neurons
Acuna, C., Obrietan, K. H., & van den Pol, A. N. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.5838-09.2010 · Cited by 61 · see citing works
“CB1Rs are often located in presynaptic structures (Glickfeld and Scanziani, 2006; Chevaleyre et al., 2007) and their activation regulates transmitter release.”
BackgroundHaj-Dahmane, S., & Shen, R.-Y. (2010) · Journal of Physiology · doi:10.1113/jphysiol.2010.190066 · Cited by 54 · see citing works
“2008) and GABA synapses (Chevaleyre et al. 2007) in other brain areas.”
BackgroundResultInfluentialKodirov, S. A., Jasiewicz, J., Amirmahani, P., Psyrakis, D., Bonni, K., Wehrmeister, M., & Lutz, B. (2009) · Learning & Memory · doi:10.1101/lm.1663410 · Cited by 51 · see citing works
“, learning and memory (Hohmann et al. 2005; Chevaleyre et al. 2007).”
Modulating excitation through plasticity at inhibitory synapses
Chevaleyre, V., & Piskorowski, R. A. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00093 · Cited by 58 · see citing works
“Consistently, protein kinase A (PKA) activity and the active zone proteins RIM1α and Rab3b are needed for iLTD induction (Chevaleyre et al., 2007; Tsetsenis et al., 2011), indicating that iLTD results in a change on the release machinery.”
Self-citationDrug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions
Zlebnik, N. E., & Cheer, J. F. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1712-16.2016 · Cited by 55 · see citing works
Hardingham, N. R., Wright, N. F., Dachtler, J., & Fox, K. D. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.018 · Cited by 48 · see citing works
“, 2004) including a role for PKA in cannabinoid-dependent depression (Chevaleyre et al., 2007).”
Endocannabinoid‐dependent plasticity at spinal nociceptor synapses
Kato, A., Punnakkal, P., Pernía‐Andrade, A. J., von Schoultz, C., Sharopov, S., Nyilas, R., Katona, I., & Zeilhofer, H. U. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2012.234229 · Cited by 49 · see citing works
“It is generally accepted that the short-term plasticity involves classical Gβγ-mediated inhibition of presynaptic voltage-gated Ca2+ channels, whereas LTD requires more intense conditioning stimulation, and additional intracellular transduction pathways such as reduced protein kinase A-dependent phosphorylation of the…”
PUFA and their derivatives in neurotransmission and synapses: a new hallmark of synaptopathies
Miceli, M. D., Bosch‐Bouju, C., & Layé, S. (2020) · Proceedings of The Nutrition Society · doi:10.1017/s0029665120000129 · Cited by 56 · see citing works
Synaptic plasticity in the auditory system: a review
Friauf, E., Fischer, A. U., & Fuhr, M. F. (2015) · Cell and Tissue Research · doi:10.1007/s00441-015-2176-x · Cited by 48 · see citing works
“The period of endocannabinoid-induced low P r can be brief (maximum at ~5–10 s; t 1/2 ~15–20 s) or last tens of minutes (Kreitzer and Regehr 2001; Chevaleyre et al. 2007).”
Lachamp, P. M., Liu, Y., & Liu, S. J. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.2354-08.2009 · Cited by 46 · see citing works
“DOI:10.1523/JNEUROSCI.2354-08.2009 Copyright © 2009 Society for Neuroscience 0270-6474/09/290381-12$15.00/0 presynaptic LTD of inhibitory transmission (Chevaleyre et al., 2007).”
BackgroundInfluentialRombo, D., Dias, R., Duarte, S., Ribeiro, J., Lamsa, K., & Sebastião, A. (2016) · Cerebral Cortex · doi:10.1093/cercor/bhu288 · Cited by 47 · see citing works
“IPSCs were evoked as described elsewhere (Chevaleyre et al. 2007) with some alterations.”
MethodKaeser-Woo, Y. J., Younts, T. J., Yang, X., Zhou, P., Wu, D., Castillo, P., & Südhof, T. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5814-12.2013 · Cited by 47 · see citing works
“Another, possibly equally important question is what molecule mediates the PKA-dependent suppression of synaptic transmission during iLTD, which is another PKA-dependent form of presynaptic long-term plasticity but does not require Syt12 (Fig.”
BackgroundInfluentialSelf-citationSilva, L., Zhao, N., Popp, S., & Dow-Edwards, D. (2011) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2011.10.006 · Cited by 47 · see citing works
“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript amygdala (Marsicano et al., 2002); (Azad et al., 2004); (Chevaleyre et al., 2007) and hippocampus (Chevaleyre et al., 2007); (Jutras-Aswad et al., 2009); (Lin et al., 2009); (Belue et al., 1994).”
BackgroundCoexistence of Multiple Types of Synaptic Plasticity in Individual Hippocampal CA1 Pyramidal Neurons
Edelmann, E., Cepeda-Prado, E., & Leßmann, V. (2017) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2017.00007 · Cited by 48 · see citing works
“However, in a related preparation the increase of neurotransmitter release in presynaptic LTP was shown to be mediated by cAMP/PKA signaling and involving the active zone protein RIM1α (Castillo et al., 2002; Chevaleyre et al., 2007; Shin et al., 2010).”
BackgroundBlundell, J. J., Kaeser, P. S., Südhof, T., & Powell, C. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0328-10.2010 · Cited by 44 · see citing works
“, 2004), and a lack of many forms of presynaptic long-term plasticity at multiple synapses in the hippocampus and in other brain areas (Castillo et al., 2002; Huang et al., 2005; Fourcaudot et al., 2006; Chevaleyre et al., 2007).”
BackgroundSelf-citationCapogna, M., Castillo, P. E., & Maffei, A. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14907 · Cited by 41 · see citing works
“However, ISP in the form of I-LTP or I-LTD is typically induced rapidly, is long-lasting (Chevaleyre et al., 2007; Nugent et al., 2007; Wang & Maffei, 2014; Woodin et al., 2003) and recruits complex post-translational mechanisms that can lead to structural and functional changes in…”
BackgroundSelf-citation
- Authors
- Chevaleyre, V., Heifets, B. D., Kaeser, P. S., Südhof, T. C., & Castillo, P. E.
- Affiliations
- Albert Einstein College of Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Castillo, Pablo E.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2007-06
- Volume
- 54
- Issue
- 5
- Pages
- 801-812
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2001295
- OpenAlex
- W2033328335
- Cited by
- 261
- References
- 0
- Citations by year
- 2026: 1 · 2025: 13 · 2024: 7 · 2023: 9 · 2022: 11 · 2021: 13 · 2020: 20 · 2019: 3 · 2018: 11 · 2017: 17 · 2016: 16 · 2015: 10 · 2014: 15 · 2013: 13 · 2012: 22
- FWCI
- 12.92
- Type
- journal article
- Language
- en
- Update notices
- erratum (2007-07-05)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Epilepsy Foundation
- National Institutes of Health
- National Institute on Drug Abuse (R01DA017392)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- endocannabinoids, CB1 receptor, long-term depression, presynaptic plasticity, cAMP/PKA signaling, active zone, synaptic inhibition, hippocampus, amygdala, G protein-coupled receptor signaling
- MeSH terms
- Cyclic AMP, Amygdala, Animals, Hippocampus, Male, Mice, Inbred C57BL, Neural Inhibition, Neural Pathways, Synaptic Transmission, Organ Culture Techniques, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Mice, Knockout, GTP-Binding Proteins, Long-Term Synaptic Depression, Receptor, Cannabinoid, CB1, Mice, Cannabinoid Receptor Modulators, Endocannabinoids
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