Synaptic plasticity is a cardinal cellular mechanism for learning and memory. 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. However, it is not known how eCB signaling may support bidirectionality. Here, we combined electrophysiology experiments with mathematical modeling to question the mechanisms of eCB bidirectionality in spike-timing dependent plasticity (STDP) at corticostriatal synapses. We demonstrate 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). Moreover, we show that eCB-tLTD requires active calcineurin whereas eCB-tLTP necessitates the activity of presynaptic PKA. Therefore, just like glutamate or GABA, eCB form a bidirectional system to encode learning and memory.DOI: http://dx.doi.org/10.7554/eLife.13185.001
In Hebbian plasticity, neural circuits adjust their synaptic weights depending on patterned firing. Spike-timing-dependent plasticity (STDP), a synaptic Hebbian learning rule, relies on the order and timing of the paired activities in pre- and postsynaptic neurons. Classically, in ex vivo experiments, STDP is assessed with deterministic (constant) spike timings and time intervals between successive pairings, thus exhibiting a regularity that differs from biological variability. Hence, STDP emergence from noisy inputs as occurring in in vivo-like firing remains unresolved. Here, we used noisy STDP pairings where the spike timing and/or interval between pairings were jittered. We explored with electrophysiology and mathematical modeling, the impact of jitter on three forms of STDP at corticostriatal synapses: NMDAR-LTP, endocannabinoid-LTD and endocannabinoid-LTP. We found that NMDAR-LTP was highly fragile to jitter, whereas endocannabinoid-plasticity appeared more resistant. When the frequency or number of pairings was increased, NMDAR-LTP became more robust and could be expressed despite strong jittering. Our results identify endocannabinoid-plasticity as a robust form of STDP, whereas the sensitivity to jitter of NMDAR-LTP varies with activity frequency. This provides new insights into the mechanisms at play during the different phases of learning and memory and the emergence of Hebbian plasticity in in vivo-like activity.
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