Astroglial type-1 cannabinoid receptor (CB1): A new player in the tripartite synapse

doi:10.1016/j.neuroscience.2015.05.002

Neuroscience

Volume 323, 26 May 2016, Pages 35-42

https://doi.org/10.1016/j.neuroscience.2015.05.002 Get rights and content

Highlights

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CB₁ receptors are present on brain astrocytes.
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Astroglial CB₁ receptors participate in the activity of the tripartite synapse.
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Astroglial CB₁ receptors mediate working memory impairments induced by cannabinoids.

Abstract

The endocannabinoid system is an important regulator of physiological functions. In the brain, this control is mainly exerted through the type-1-cannabinoid (CB₁) receptors. CB₁ receptors are abundant at neuron terminals where their stimulation inhibits neurotransmitter release. However, CB₁ receptors are also expressed in astrocytes and recent studies showed that astroglial cannabinoid signaling is a key element of the tripartite synapse. In this review we discuss the different mechanisms by which astroglial CB₁ receptors control synaptic transmission and plasticity. The recent involvement of astroglial CB₁ receptors in the effects of cannabinoids on memory highlights their key roles in cognitive processes and further indicates that astrocytes are central active elements of high-order brain functions.

Introduction

The discovery of the endocannabinoid system (ECS) as the endogenous target of the main active compound of the plant cannabis sativa (Marijuana), Δ⁹-tetrahydrocannabinol (THC), revealed a complex and multimodal system involved in the regulation of many physiological processes (Piomelli, 2003, Kano et al., 2009).

The ECS is broadly present in the body (Piomelli, 2003, Pacher et al., 2006) and is composed of cannabinoid receptors (mainly CB₁ and CB₂), their endogenous lipophilic ligands called endocannabinoids (eCBs), including 2-arachidonoylglycerol (2-AG) and anandamide (AEA), and the enzymatic machinery responsible for eCBs production and degradation (Piomelli, 2003). Both CB₁ and CB₂ receptors are present in the central nervous system (CNS) and their activity directly affects glial functions (Stella, 2010). However, CB₁ receptors are the most important responsible elements of (endo)cannabinoid effects and functions in the CNS. Thus, for the sake of brevity, this review will focus on the astroglial roles of CB₁ receptors and we refer the reader to recent reviews describing the role of CB₂ receptors and other elements of the ECS in glial cells (Walter and Stella, 2004, Stella, 2009, Stella, 2010).

CB₁ receptors have been extensively described at the membrane of neuronal presynaptic terminals, where they are responsible for intracellular mechanisms leading to retrograde inhibition of neurotransmitter release (Piomelli, 2003, Kano et al., 2009, Castillo et al., 2012). Yet, during the last decade, an increasing number of studies reported the presence of CB₁ receptors at other locations such as postsynaptic terminals (Bacci et al., 2004, Marinelli et al., 2009), intracellular organelles such as mitochondria (Benard et al., 2012) and also on astrocytes (Navarrete and Araque, 2008, Navarrete and Araque, 2010, Han et al., 2012) although their functional roles at these locations are far from being completely understood.

Astrocytes constitute the large majority of glial cells in the CNS, and they are mainly thought to metabolically support neurons and to keep a stable homeostatic environment for correct neuronal functions (Magistretti, 2006, Belanger and Magistretti, 2009). Despite their lack of electrical properties, astrocytes are highly organized and can communicate among themselves through extensive networks (Giaume et al., 2010). Moreover, in the past 15 years, it has been proposed that astrocytes were not mere supporters of neuronal survival and functions, but they could also be part of bidirectional communication with neurons (Araque et al., 1999). This growing view of astrocytes as powerful integrators of synaptic information together with recent findings linking ECS and astroglial functions lead to an outlook where the ECS might be a key modulator of astrocytic activity (Navarrete et al., 2014, Metna-Laurent and Marsicano, 2015).

In this review, we describe the presence of the ECS in astrocytes and its known roles in some astrocytic functions. Particularly, we discuss the role played by CB₁ receptors in the modulation of the electrophysiological activity of the tripartite synapse in the brain and its potential impact on behavioral processes.

Section snippets

Introduction to the tripartite synapse

Because astrocytes are unable to generate action potentials, it was thought for a long time that these cells did not take part in the exchange or integration of information in the CNS but rather had a passive and structural role (Koob, 2009). However, it is now clear that astrocytes form, together with pre- and post-synaptic neurons, an important functional entity that has been called the tripartite synapse (Araque et al., 1999). The concept of tripartite synapse has been recently reviewed (

The ECS in astrocytes

CB₁ receptors are likely the most abundant GPCRs in the brain (Herkenham et al., 1990) and they are widely expressed in several brain regions such as the hippocampus, the neocortex, the amygdala, the striatum, the substantia nigra, the hypothalamus, the cerebellum and the brainstem (Marsicano and Kuner, 2008, Kano et al., 2009). Classically, CB₁ receptors are described as mainly present in the presynaptic terminals, mostly of GABAergic interneurons, but also, although at lower levels, on many

Astroglial CB₁ receptor signaling in the tripartite synapse – electrophysiological evidence

The broad range of overlapping physiological functions modulated by the ECS and astrocytes suggests their close functional association in vast domains such as energy and metabolism, neuroprotection and synaptic plasticity (Metna-Laurent and Marsicano, 2015). Regarding the purposes of this review, we will limit our discussion to the role played by the ECS in the modulation of synaptic transmission through astrocytes.

As previously described, the neuron–astroglial interactions represented in the

Role of astroglial CB₁ receptors in behavioral functions

The characterization of exogenous cannabinoids, and later of the ECS, brought an impressive number of experimental studies characterizing on the one hand the behavioral consequences of exogenous cannabinoids administration, and on the other hand the endogenous functions of the ECS in behavioral processes. Indeed, CB₁ receptors have been implicated in many behaviors including the control of food intake, of emotion- motivation- and stress-related responses, as well as the expression of cognitive

Conclusion

In this short review, we addressed the growing importance of CB₁ receptors expressed in astroglial cells in the regulation of synaptic transmission and plasticity and its likely consequences at behavioral level. The interactions between the ECS and astrocytes are mostly unexplored with many interesting questions to be addressed (Box 1). Their role in the regulation of high-order brain functions is a very exciting and new field of research, which will provide interesting surprises in the next

Acknowledgments

We thank all the members of Marsicano’s lab for useful discussions. This work was supported by INSERM (G.M.), EU–Fp7 (PAINCAGE, HEALTH-603191, G.M.), European Research Council (Endofood, ERC–2010–StG–260515, G.M.; CannaPreg, ERC-2014-PoC-640923), Fondation pour la Recherche Medicale (DRM20101220445, G.M.), Human Frontiers Science Program (G.M.), International PhD School of the University of Catania (J.O.C.) Region Aquitaine (G.M.), BRAIN ANR-10-LABX-0043 (G.M.).

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^†: These authors equally contributed to this work.

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ReviewAstroglial type-1 cannabinoid receptor (CB1): A new player in the tripartite synapse

Highlights

Abstract

Introduction

Section snippets

Introduction to the tripartite synapse

The ECS in astrocytes

Astroglial CB1 receptor signaling in the tripartite synapse – electrophysiological evidence

Role of astroglial CB1 receptors in behavioral functions

Conclusion

Acknowledgments

Neuron

Trends Neurosci

Mol Metab

Toxicon

Neuron

Neuron

Life Sci

Cell

Prostaglandins Other Lipid Mediat

Peptides

Neuron

Neuron

Cell

Brain Res Rev

Neuron

Neuropharmacology

Cell

Mol Cell Endocrinol

Adult neurogenesis: from precursors to network and physiology

Physiol Rev

Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids

Nature

The role of astroglia in neuroprotection

Dialogues Clin Neurosci

Bimodal control of stimulated food intake by the endocannabinoid system

Nat Neurosci

Opposite control of frontocortical 2-arachidonoylglycerol turnover rate by cannabinoid type-1 receptors located on glutamatergic neurons and on astrocytes

J Neurochem

Mitochondrial CB(1) receptors regulate neuronal energy metabolism

Nat Neurosci

Adult neurogenesis: basic concepts of signaling

Cell Cycle

Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains

J Neurosci

Endocannabinoid-mediated synaptic plasticity in the CNS

Annu Rev Neurosci

Local Ca2+ detection and modulation of synaptic release by astrocytes

Nat Neurosci

The endocannabinoid system and its therapeutic exploitation

Nat Rev Drug Discov

Genetic dissection of the role of cannabinoid type-1 receptors in the emotional consequences of repeated social stress in mice

Neuropsychopharmacology

Mechanisms of control of neuron survival by the endocannabinoid system

Curr Pharm Des

Review
Astroglial type-1 cannabinoid receptor (CB₁): A new player in the tripartite synapse

Astroglial CB₁ receptor signaling in the tripartite synapse – electrophysiological evidence

Role of astroglial CB₁ receptors in behavioral functions

Local Ca²⁺ detection and modulation of synaptic release by astrocytes