Section: New Results

Dopamine-endocannabinoid interactions mediate spike-timing dependent potentiation in the striatum

Participants: Hugues Berry, Alexandre Foncelle, Ilya Prokin

Synaptic long-term plasticity underlies multiple forms of learning and memory in the brain. In most systems, its bidirectionality - depression (LTD) and potentiation (LTP) allows adaptive adjustment of the synaptic weight depending on the activity. Endocannabinoids (eCBs), one of the most widespread neurotransmitter systems, are very well established as depressing neuronal communication but recent experimental evidence challenges this depression-only vision. Our previous work in collaboration with L. Venance's lab at CIRB, College de France, Paris (experimental neuroscience) has combined experimental and mathematical modeling approaches to identify in the basal ganglia the existence of an eCB-mediated spike-timing dependent LTP (eCB-tLTP) induced by a low number of paired stimulations [50], [49]. However, the regulation and control mechanisms of eCB-tLTP remained unknown. Using the same combination of experimental and modelling approaches, we have now discovered that dopamine controls eCB-tLTP. The dopamine system is a key actor of associative learning in the basal ganglia and a pivotal system in several pathologies including Parkinson's disease. We identified that eCB-tLTP depends on dopamine and involves the activation of D2R dopamine receptors located presynaptically in corticostriatal glutamatergic afferents. We moreover show that dopamine control of eCB-tLTP is of pathological significance since it is impaired in a rodent model of Parkinson’s disease and rescued by chronic L-DOPA treatment in those animals. Combining our experimental finding with a realistic mathematical model of the underlying signaling pathway, we could describe the mechanisms accounting for this endocannabinoid-dopamine regulation of eCB-tLTP.

This result is currently under review in the journal Nature Communications.