Programming of Neural Cells by (Endo)Cannabinoids: from Physiological Rules to Emerging Therapies
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REVIEWS THE ENDOCANNABINOID SYSTEM Programming of neural cells by (endo) cannabinoids: from physiological rules to emerging therapies Mauro Maccarrone1,2, Manuel Guzmán3, Ken Mackie4, Patrick Doherty5 and Tibor Harkany6,7 Abstract | Among the many signalling lipids, endocannabinoids are increasingly recognized for their important roles in neuronal and glial development. Recent experimental evidence suggests that, during neuronal differentiation, endocannabinoid signalling undergoes a fundamental switch from the prenatal determination of cell fate to the homeostatic regulation of synaptic neurotransmission and bioenergetics in the mature nervous system. These studies also offer novel insights into neuropsychiatric disease mechanisms and contribute to the public debate about the benefits and the risks of cannabis use during pregnancy and in adolescence. Morphogenetic signals The capacity of the brain for information processing endocannabinoid signalling seems to be a multimodal Gradients of molecules that relies on the number and the molecular and functional communication cassette that is involved in pattern- determine the position of diversity of neurons, their topographically precise con- ing neuronal connections, the synaptic efficacy of specialized cellular subtypes nectivity and their metabolic and signalling interac- which, once they are mature, is often also modulated and instruct their 7 communication and functional tions with glial cells. The developing nervous system by endocannabinoids (FIG. 1a). The widespread nature role during histogenesis. encompasses a range of interacting signalling path- of endocannabinoid modulation of both excitatory and ways, which are individually controlled along unique inhibitory synaptic neurotransmission in the postnatal Sphingolipids temporal and spatial scales. During brain development, brain9 and spinal cord13 (FIG. 1b) suggests that develop- Molecules that contain the organic aliphatic amino alcohol neural progenitor cell proliferation and asymmetric mental rules might place these small signalling lipids into sphingosine or a structurally division, and the positioning and molecular diversifi- a crucial arch of the molecular machinery controlling similar molecule as a cation of neuronal and glial progenies, are modulated synaptic neurotransmission. backbone. by both cell-autonomous and cell–cell interactions of The family of endocannabinoids and their structural morphogenetic signals that are crucial to building com- analogues14 potentially includes hundreds of bioactive Endocannabinoids Endogenous compounds that plex tissues. Among these structurally and functionally molecules. This Review focuses on 2-arachidonoylglyc- bind to cannabinoid 1 diverse signalling domains, bioactive signalling lipids erol (2-AG), which is the most abundant mammalian receptors (CB1Rs) and/or (for example, phospholipids, sphingolipids, glycolipids endocannabinoid that affects synaptic neurotransmis- CB2Rs with high affinity, and and prostanoids) are widely recognized as crucial for sion15,16, and to a lesser extent on anandamide (AEA)17, are able to evoke a 9 neuronal and glial differentiation, as well as for synaptic which is a mixed endovanilloid and endocannabinoid Δ -tetrahydrocannabinol-like 1–3 behavioural tetrad. plasticity . ligand. 2-AG, AEA and related lipids can stimulate Recent work has highlighted similar but unexpect- cannabinoid 1 receptors (CB1Rs) and CB2Rs and the edly diverse roles in the developing nervous system nuclear fatty acid receptors peroxisome proliferator- for the endocannabinoid family of small signalling activated receptor-α (PPARα) and PPARγ (REF. 18). lipids, N-acyl-amines and 2-acyl-glycerols, which 2-AG generally has higher efficacy at CB1R and CB2R, typically contain an arachidonoyl moiety4,5. Indeed, whereas AEA is a low-efficacy agonist that can function Correspondence to evidence suggests that there is a continuum of action as a partial agonist (or even antagonist) in tissues with M.M. and T.H. by endocannabinoids, overarching the early stages of low receptor reserve or at receptors that are inefficiently e-mails: m.maccarrone@ embryo development and implantation6, nervous sys- coupled to downstream effectors. AEA and 2-AG can unicampus.it; Tibor. 7 8 Harkany@ki.se; Tibor. tem development , bioenergetics and intercellular stimulate PPARs at high concentrations, although 9,10 Harkany@meduniwien.ac.at communication in the adult, including adult neu- related molecules such as N-oleoylethanolamine do so doi:10.1038/nrn3846 rogenesis11,12. More specifically for the nervous system, more potently. Moreover, AEA can engage transient 786 | DECEMBER 2014 | VOLUME 15 www.nature.com/reviews/neuro © 2014 Macmillan Publishers Limited. All rights reserved REVIEWS sn-1-diacylglycerol lipase-α receptor potential cation channel subfamily V mem- gliomas. Finally, we highlight differential sensitivities of (DAGLα). Two isoforms of ber 1 (TRPV1) and G protein-coupled receptor 55 precisely controlled physiological processes versus dis- DAGL, DAGLα and DAGLβ, (GPR55)18. ease pathomechanisms to help to put the ongoing public which probably evolved Although gaps persist in our knowledge of endocan- debate about the use of Δ9-THC during pregnancy and in evolutionarily through gene duplication, are chiefly nabinoid action during formation of the subcortical adolescents into a more realistic context. responsible for 2-AG forebrain, midbrain and spinal cord, the studies high- synthesis. lighted in this section define multiple steps of cortical Molecular logic of endocannabinoid action and cerebellar development modulated by endocan- Much of what we know about the molecular organization Tripartite synapse nabinoids, which have been elucidated through the use of endocannabinoid signalling during neuronal develop- A concept of synaptic 19–24 FIG. 1a anatomy that includes the of an impressive range of genetic and cellular tools ment (schematically depicted in ) comes from the 25,26 presynaptic terminal, and evolutionary deductions , as well as experimen- comparative analysis of successive developmental stages postsynaptic specialization tal models in invertebrates27, non-mammalian verte- in rodents11,22,32,33,46,48 (FIG. 2a–d). Arrangements at mature and astroglial end-feet that brates28,29, rodents30–34 and human foetal tissues35–38. synapses are such that 2-AG synthesis is postsynap- isolate the synaptic cleft as a 15,16,49 sn-1-diacylglycerol lipase- discrete entity. The evidence for endocannabinoid involvement in tic with α (DAGLα) enriched fundamental developmental processes comes from the in the ‘perisynaptic annulus’ (that is, 50–100 nm from combination of sophisticated mouse genetics21,39, neu- the postsynaptic density50), which allows the fast cou- rophysiology40 and the study of gene polymorphisms pling of postsynaptic metabotropic receptor activation for CB1R, CB2R, α/β-hydrolase domain-containing to Ca2+ and phospholipase Cβ-dependent 2-AG synthe- 12 (ABHD12) and fatty acid amide hydrolase (FAAH) sis51 (FIG. 1b). Diffusing in a retrograde manner across the in humans with diseases that are thought to have a synapse, endocannabinoids activate presynaptic CB1Rs, developmental origin, such as schizophrenia, bipolar typically signalling via Gi proteins to inhibit synaptic neu- disorder, drug addiction, metabolic disorders and rotransmission (FIG. 1b). 2-AG is then mainly inactivated neurodegeneration41–45. These studies support causality by presynaptic monoacylglycerol lipase (MAGL)52, with between dysregulated endocannabinoid signalling and a possible contribution from ABHD6 and ABHD12 (REFS neuropsychiatric illnesses. Thus, the interdisciplinary 45,53), which are partitioned to postsynaptic sites (FIG. 1b). nature of this Review provides a translational frame- The situation with AEA is more complex. AEA can be work that bridges (at least) two key areas of neuro produced postsynaptically to inhibit synaptic transmis- science: neurophysiology; and psychiatric and addiction sion in a retrograde manner as in the case of 2-AG54. research. Alternatively, N-arachidonoylethanolamine-selective Endocannabinoid signalling at CB1R and CB2R in phospholipase D (NAPE-PLD) may produce AEA neural progenitor cells and postmitotic neurons11,24,46 presynaptically, which then functions at postsynaptic is recognized as the primary molecular substrate for TRPV1 (REFS 55,56) and is inactivated by postsynaptic phytocannabinoids47, most prominently for psycho FAAH57. Notably, and in accordance with the tripartite active Δ9-tetrahydrocannabinol (Δ9-THC). In this synapse hypothesis, perisynaptic astrocytes often con- context, and after discussing the multifarious roles of tain MAGL (FIG. 1b), thus forming a barrier that may endocannabinoid signalling in the prenatal and peri- limit 2-AG spread beyond its intended site of action natal brain, we address endocannabinoid contributions (20–100 µm in a temperature-sensitive manner)58,59. to regulating adult neurogenesis, as cannabis use might At least four premises should be considered to appre- affect the continued production of new neurons in ado- ciate the unique modes of endocannabinoid signal- lescents. We examine the molecular mechanisms and ling during brain development, and these are discussed the health benefits of exploiting the endocannabinoid in this section. First, in differentiating neural tissues, system as a druggable target in pathologies that arise endocannabinoids can adopt a primarily autocrine (cell- from the loss of cell proliferation control,