Research Highlight: Endocannabinoid dynamics gate spike-timing dependent depression and potentiation

Yihui CUI (ENP Alumnus) and Laurent VENANCE (ENP team leader, CIRB, College de France) have published a study in eLife “Endocannabinoid dynamics gate spike-timing dependent depression and potentiation” showing a new form of synaptic plasticity which could account for fast learning. Using a combination of electrophysiology and mathematical modeling we elucidate how endocannabinoids can encode for bidirectional Hebbian plasticity.  

Learning and memory depend on processes that alter the connections – or synapses – between neurons in the brain. The endocannabinoid (eCB) system has emerged as a pivotal pathway for synaptic plasticity because of its widely characterized ability to depress synaptic transmission on short- and long-term scales. Recent reports indicate that eCBs also mediate potentiation of the synapse. But how do endocannabinoids manage to produce opposing effects?

Using spike-timing dependent plasticity (STDP), a synaptic Hebbian learning rule which depends on the activity on either side of the synapse, we report a new form of plasticity: a striatal spike-timing dependent potentiation induced by few coincident pre- and post-synaptic spikes, mediated by eCBs. By combining electrophysiological approaches (multi-patch-clamp recordings) and mathematical modeling (realistic biophysical model, in coll. with H Berry, INRIA), we have now deciphered the molecular mechanisms that govern the action of eCBs cortico-striatal synapses in rodent brain slices. This revealed that both the levels and timing of endocannabinoid release control changes in the strength of the synaptic connections. Activity patterns that produced moderate amounts of endocannabinoids over a prolonged period led to synaptic depression. However, activity that produced short but large endocannabinoid peaks caused synaptic potentiation. The enzymes that control endocannabinoid levels thus play a crucial role in determining whether a given stimulation leads to the strengthening or weakening of a synaptic connection.

Altogether, our results show that eCB bidirectional plasticity constitutes a versatile system, which operation may underlie a complex repertoire of learning abilities, depending on activity pattern at corticostriatal circuits and on the behavioral context.

Check out the article: 

Endocannabinoid dynamics gate spike-timing dependent depression and potentiation. Yihui Cui, Ilya Prokin, Hao Xu, Bruno Delord, Stephane Genet,Laurent Venance*, Hugues Berry*.

eLife 2016;5:e13185. DOI: 10.7554/eLife.13185

Figure: The mathematical model matches the experimental data for STDP Changes of the total synaptic weight Wtotal (LTP and LTD) when Npairings and ΔtSTDPvary. Color-coded changes of Wtotal in the (N, ΔtSTDP) space. The color bar indicates the color code. The background map shows the simulation results whereas the color-coded points (same color-code as the simulations) are experimental results.