Section: New Results

Deciphering the signalling networks of synaptic plasticity

Synaptic plasticity, i.e. adaptive modifications of synaptic strength between two neurons depending on their activity, is a main substrate for learning and memory. Experimentally, synaptic plasticity is commonly assessed using prolonged electrical stimulations. Since learning can arise from few or even a single trial, synaptic strength is expected to adapt rapidly. However, whether synaptic plasticity occurs in response to limited event occurrences remains elusive. To address this question, we started a collaboration with Laurent Venance Lab (experimental neuroscience, College de France, Paris). Combining experimental and modelling approaches, we investigated whether a low number of stimulations can induce plasticity in a major synaptic learning rule, spike-timing-dependent plasticity (STDP). It is known that 100 stimulations induce bidirectional STDP, i.e. spike-timing-dependent potentiation (tLTP) and depression (tLTD) at most central synapses. In rodent striatum, we found that tLTD progressively disappears when the number of stimulations is decreased (below 50 pairings) whereas tLTP displays a biphasic profile: tLTP is observed for 75-100 stimulations, absent for 25-50 stimulations and re-emerges for 5-10 stimulations. This tLTP, induced by very few stimulations (5-10) depends on the endocannabinoid (eCB) system. The eCB system has recently emerged as a pivotal pathway for synaptic plasticity because of its widely characterized ability to depress synaptic transmission on short- and long-term scales. Our result therefore indicate that eCBs also mediate potentiation of the synapse. To understand how eCB signaling may support such bidirectionality, we combined electrophysiology experiments with mathematical modeling. Our model describes the temporal kinetics of the biochemical species involved in a first signaling pathway leading from NMDAR to calmodulin and CaMKII with that of a a second, distinct one that assembles mGluR and cytosolic calcium to eCB production and the resulting activation of CB1R. This demonstrated that STDP outcome is controlled by eCB levels and dynamics: prolonged and moderate levels of eCB lead to eCB-mediated long-term depression (eCB- tLTD) while short and large eCB transients produce eCB-mediated long-term potentiation (eCB-tLTP). Therefore, just like neurotransmitters glutamate or GABA, eCB forms a bidirectional system to encode learning and memory.

For reasons of publication strategy, our first co-publication on the subject presents our major experimental results [16] . A second article, featuring both experimental and modelling results, explains how the underlying signalling network can support the observed bidirectionality and is under submission.