Endocannabinoids mediate bidirectional striatal spike‐timing‐dependent plasticity

Abstract

Key pointsr Although learning can arise from few or even a single trial, synaptic plasticity is commonly assessed under prolonged activation. Here, we explored the existence of rapid responsiveness of synaptic plasticity at corticostriatal synapses in a major synaptic learning rule, spike-timing-dependent plasticity (STDP).r We found that spike-timing-dependent depression (tLTD) progressively disappears when the number of paired stimulations (below 50 pairings) is decreased whereas spike-timing-dependent potentiation (tLTP) displays a biphasic profile: tLTP is observed for 75-100 pairings, is absent for 25-50 pairings and re-emerges for 5-10 pairings. r Endocannabinoid-tLTP may represent a physiological mechanism operating during the rapid learning of new associative memories and behavioural rules characterizing the flexible behaviour of mammals or during the initial stages of habit learning.Abstract Synaptic plasticity, a main substrate for learning and memory, is commonly assessed with prolonged 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 answer this question, we investigated whether a low number of paired stimulations can induce plasticity in a major synaptic learning rule, spike-timing-dependent plasticity (STDP). It is known that 100 pairings 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 paired stimulations is decreased (below 50 pairings) whereas tLTP displays a biphasic profile: tLTP is observed for 75-100 pairings, absent for 25-50 pairings and re-emerges for 5-10 pairings. This tLTP, induced by very few pairings (ß5-10) depends on the endocannabinoid (eCB) system. This eCB-dependent tLTP (eCB-tLTP) involves postsynaptic endocannabinoid synthesis, requires paired activity (post-and presynaptic) and the activation of type-1 cannabinoid receptor (CB1R) and transient receptor potential vanilloid type-1 (TRPV1). eCB-tLTP occurs in both striatopallidal and striatonigral medium-sized spiny neurons (MSNs) and is dopamine dependent. Lastly, we show that eCB-LTP and eCB-LTD can be induced sequentially in the same neuron, depending on the cellular conditioning protocol. Thus, while endocannabinoids are usually thought simply to depress synaptic function, they also constitute a versatile system underlying bidirectional plasticity. Our results reveal a novel form of synaptic plasticity, eCB-tLTP, which may underlie rapid learning capabilities characterizing behavioural flexibility.

Synaptic functions of endocannabinoid signaling in health and disease

“…eCBs also promote LTP via both CB 1 and TRPV1 and on 2-AG elevations (Cui et al, 2015; Cui et al, 2016). The emerging picture is that eCBs are bidirectional rather than unidirectional neuromodulators of striatal functions.…”

Closing the gap: long-term presynaptic plasticity in brain function and disease

“…At MF-CA3 interneuron synapses, presynaptic mGluR7 can act as a metaplastic switch to control the sign of plasticity by regulating cAMP sensitivity [9, 10]. While endocannabinoids (eCBs) typically mediate presynaptic LTD (eCB-LTD) [11], recent evidence suggests eCBs support bidirectionality (eCB-LTP) at cortico-striatal synapses [12, 13]. While some synapses express either presynaptic LTP or LTD, bidirectional presynaptic plasticity may be an important way to increase the dynamic range of synaptic transmission in response to experience.…”

Dietary Omega-6/Omega-3 and Endocannabinoids: Implications for Brain Health and Diseases

“…This general principle of action of endocannabinoid at the synapse is developed in a wide variety of mechanisms, depending on the structure and the triggering event, and it induces plasticity phenomenon lasting for seconds to hours [33,56,114] but always in the direction of a decrease of synaptic efficacy. Very recent studies suggest that endocannabinoids can also act to increase synaptic efficacy [115,116], but mechanisms remain unclear so it can be an indirect consequence of an endocannabinoid activation.…”