Lights on Endocannabinoid-Mediated Synaptic Potentiation.

Charlotte Piette,Nicolas Gervasi,Yihui Cui,Laurent Venance

doi:10.3389/fnmol.2020.00132

Abstract

The endocannabinoid (eCB) system is a lipid-based neurotransmitter complex that plays crucial roles in the neural control of learning and memory. The current model of eCB-mediated retrograde signaling is that eCBs released from postsynaptic elements travel retrogradely to presynaptic axon terminals, where they activate cannabinoid type-1 receptors (CB1Rs) and ultimately decrease neurotransmitter release on a short- or long-term scale. An increasing body of evidence has enlarged this view and shows that eCBs, besides depressing synaptic transmission, are also able to increase neurotransmitter release at multiple synapses of the brain. This indicates that eCBs act as bidirectional regulators of synaptic transmission and plasticity. Recently, studies unveiled links between the expression of eCB-mediated long-term potentiation (eCB-LTP) and learning, and between its dysregulation and several pathologies. In this review article, we first distinguish the various forms of eCB-LTP based on their mechanisms, resulting from homosynaptically or heterosynaptically-mediated processes. Next, we consider the neuromodulation of eCB-LTP, its behavioral impact on learning and memory, and finally, eCB-LTP disruptions in various pathologies and its potential as a therapeutic target in disorders such as stress coping, addiction, Alzheimer’s and Parkinson’s disease, and pain. Cannabis is gaining popularity as a recreational substance as well as a medicine, and multiple eCB-based drugs are under development. In this context, it is critical to understand eCB-mediated signaling in its multi-faceted complexity. Indeed, the bidirectional nature of eCB-based neuromodulation may offer an important key to interpret the functions of the eCB system and how it is impacted by cannabis and other drugs.

Highlights

In light of recent studies, this review aims at highlighting evidence for short and long-term eCB-mediated synaptic potentiation
Using spike-timing-dependent plasticity (STDP), a Hebbian synaptic learning rule relying on paired activity on either side of the synapses (Feldman, 2012), a few numbers of pairings induce eCB-long-term potentiation (LTP) at corticostriatal synapses, which is cannabinoid type-1 receptors (CB1R)- and transient receptor potential vanilloid type-1 (TRPV1)-mediated (Cui et al, 2015, 2016, 2018a; Xu et al, 2018; Figure 1A). 2-AG levels and subsequent CB1R activation have a dual effect on eCB-plasticity: high levels of eCBs synthesis and CB1R activation induce eCB-LTP, while low levels induce eCB-long-term depression (LTD) (Cui et al, 2015, 2016)
A long-lasting enhancement of inhibitory transmission observed in cortical neurons ex vivo after training on a difficult olfactory discrimination task relies on an unusual eCB-mediated mechanism: post-synaptic persistent CB1R activation in pyramidal cells leads to an inhibition of protein kinase-A (pkA), which induces an increase in postsynaptic GABAA channel conductance (Ghosh et al, 2018)

Summary

BACKGROUND

Endocannabinoids (eCBs) are a family molecule of biolipids, mainly composed by 2-arachidonoylglycerol (2-AG) and anandamide, synthesized and released on-demand, which mostly act on presynaptic cannabinoid type-1 receptors (CB1R) and postsynaptic transient receptor potential vanilloid type-1 (TRPV1; Piomelli et al, 2007; Castillo et al, 2012; Katona and Freund, 2012; Araque et al, 2017). eCBs have emerged as a major signaling system in learning and memory (Marsicano and Lafenêtre, 2009; Mechoulam and Parker, 2013; KrukSlomka et al, 2017) because of their powerful influence on synaptic plasticity, mainly as a depressing synaptic function (Castillo et al, 2012; Araque et al, 2017; Augustin and Lovinger, 2018). eCB signaling has been widely described to decrease the neurotransmitter release probability via diverse presynaptic mechanisms, including inhibition of voltage-gated calcium channels, activation of potassium channels, and protein kinase-A (pkA) signaling. Via Astrocytes eCBs, released from a given stimulated CA3–CA1 synapse, activate astrocytic CB1R and via an IP3-induced calciumrelease mechanism promote astrocytic glutamate release, which in turn induces an NMDAR-mediated short- (Navarrete and Araque, 2008, 2010) or nitric oxide(NO)-mediated long-term (Gómez-Gonzalo et al, 2015) potentiation on neighboring CA1 synapses (Figure 1B) This lateral synaptic regulation achieved by astrocytes and eCBs (Covelo and Araque, 2016), reported in the dorsal striatum (Martín et al, 2015), appears as a means of controlling distant synapses by activated ones. A long-lasting enhancement of inhibitory transmission observed in cortical neurons ex vivo after training on a difficult olfactory discrimination task relies on an unusual eCB-mediated mechanism: post-synaptic persistent CB1R activation in pyramidal cells leads to an inhibition of pkA, which induces an increase in postsynaptic GABAA channel conductance (Ghosh et al, 2018). Most of the dysregulation of eCB-mediated LTP described below involve heterosynaptic facilitation of LTP through disinhibitory mechanisms

Stress Coping

Drug Addiction

CONCLUSIONS

AUTHOR CONTRIBUTIONS