Skip to main content
  • Oral presentation
  • Open access
  • Published:

Endocannabinoids mediate spike-timing dependent potentiation and depression: a model-based experimental approach

Activity-dependent long-term potentiation (LTP) and depression (LTD) of synaptic strength underlie multiple forms of learning and memory. Endocannabinoids (eCBs) have consistently been described as mediators of short- or long-term synaptic depression through the activation of the endocannabinoid-type-1 receptor (CB1R) or the transient receptor potential vanilloid-type-1 (TRPV1). Here we investigated whether eCBs could also promote long-term potentiation, an essential requirement for eCBs to be a genuine bidirectional system and to fully encode for learning and memory.

To this aim, we combined in vitro spike timing-dependent plasticity (STDP) protocols in rodents and a biophysical model of the signaling pathways likely to be involved. The model describes the temporal dynamics of three main signaling systems: the postsynaptic NMDAR-CaMKII pathway (adapted from [1]), the postsynaptic mGluR-PLCβ system (adapted from [2]) as well as postsynaptic eCB synthesis and subsequent activation of postsynaptic TRPV1 and presynaptic CB1R in a retrograde fashion. Using the model to drive the experiments, we uncovered the existence of an eCB-mediated spike-timing dependent potentiation (eCB-LTP). This eCB-LTP is homosynaptic, astrocyte-independent and expressed in young and adult animals and across various brain regions (cortex and striatum), supporting its role as a widespread signaling system for spike-based plasticity. We deciphered the signaling pathways (pre- and postsynaptic receptors and enzymes) involved in this new form of plasticity and demonstrated that eCB plasticity has a postynaptic induction and a presynaptic maintenance. On the postsynaptic side, our results show that the dynamics of free cytosolic calcium is a key element for eCB-LTP induction. eCB-LTP is triggered when eCB transients reach sufficiently high levels. Since the enzymes that synthetize eCBs are calcium-activated, eCB-LTP induction requires large levels of cytosolic calcium. On the presynaptic side, eCBs encode for bidirectional plasticity via a triad composed of eCB levels, presynaptic PKA and presynaptic CaN: intermediate eCB levels promote presynaptic CaN activity, that yields eCB-LTD, whereas large eCB amplitudes favor presynaptic PKA activity, which leads to eCB-LTP. Both effects are predicted to rely on the inhibition exerted by activated CB1R on presynaptic adenylate cyclase and P/Q-type voltage-gated calcium channels. Moreover, we show that eCB-LTP and eCB-LTD can be induced sequentially in the same neuron, depending on the cellular conditioning paradigm. Therefore, our results demonstrate that eCBs, just like glutamatergic or GABAergic signaling, form a generic system able to encode for bidirectional plasticity and capable of genuine homeostasis.

Lastly, we found that eCB-LTP is triggered by very few paired spikes (5 to 10 post-pre spikes at 1 Hz are enough). Thus, eCB-LTP provides synapses with a mechanism able to react to the very first occurrences of incoming activity. This ability strongly contrasts with NMDAR-dependent LTP which, in a classical (1 Hz) STDP context, requires the iteration of at least 75-100 paired stimulations to be expressed, at odds with the observations that new associative memories and behavioral rules can be learned within few or even a single trials in mammals (e.g. [3]). Our results suggest that eCB-LTP may represent a neuronal substrate for such rapid learning abilities.


  1. Graupner M, Brunel N: STDP in a bistable synapse model based on CaMKII and associated signaling pathways. PLoS Comput Biol. 2007, 3: e221-10.1371/journal.pcbi.0030221.

    Article  PubMed Central  PubMed  Google Scholar 

  2. De Pittà M, Goldberg M, Volman V, Berry H, Ben-Jacob E: Glutamate regulation of calcium and IP3 oscillating and pulsating dynamics in astrocytes. J Biol Phys. 2009, 35: 383-411. 10.1007/s10867-009-9155-y.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Pasupathy A, Miller EK: Different time courses of learning-related activity in the prefrontal cortex and striatum. Nature. 2005, 433: 873-876. 10.1038/nature03287.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Laurent Venance or Hugues Berry.

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Cui, Y., Paille, V., Delord, B. et al. Endocannabinoids mediate spike-timing dependent potentiation and depression: a model-based experimental approach. BMC Neurosci 14 (Suppl 1), O1 (2013).

Download citation

  • Published:

  • DOI: