Article series: The endocannabinoid system

Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies

Journal name:
Nature Reviews Neuroscience
Year published:
Published online


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.

At a glance


  1. Molecular architecture of the endocannabinoid system during synaptogenesis and at mature synapses.
    Figure 1: Molecular architecture of the endocannabinoid system during synaptogenesis and at mature synapses.

    Neuronal and glial components of developing and mature synapses are shown. The molecular architecture shown here is for a 'stereotypical' synapse that uses endocannabinoid signalling. There are differences in neurotransmitter system-specific and developmentally regulated enzyme and/or receptor expression and function at different types of synapse and at different stages of development. For example, monoacylglycerol lipase (MAGL) is excluded from motile growth cones until synaptogenesis commences48, 68. a | At the developing synapse, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) initiate downstream signalling by binding to their target receptors: cannabinoid 1 receptor (CB1R), CB2R, G protein-coupled receptor 55 (GPR55) and transient receptor potential cation channel subfamily V member 1 (TRPV1). Their availability is determined by biosynthesis enzymes (N-acylphosphatidylethanolamine-specific phospholipase D, NAPE-PLD, sn-1-diacylglycerol lipase-α (DAGLα) and DAGLβ195) and degrading enzymes (fatty acid amide hydrolase (FAAH) and MAGL). It is not yet known whether alternative hydrolysis enzymes (for example, α/β-hydrolase domain-containing 6 (ABHD6) and ABHD12) also play a part at this stage in development. Unlike other endocannabinoid-binding receptors, CB1Rs are preferentially recruited to, and signal within, cholesterol-enriched membrane microdomains termed lipid rafts62. b | At the mature synapse, the availability of AEA and 2-AG is controlled by ABHD6 and ABHD12 hydrolases, in addition to FAAH and MAGL, and also by transmembrane (endocannabinoid transmembrane transporter (EMT)) and intracellular (AEA intracellular transporter (AIT)) transport mechanisms196 (for example, fatty acid-binding proteins199, heat shock protein 70 (Ref. 197) and FAAH-like AEA transporter198) and storage organelles (adiposomes or lipid droplets)199. There is compelling evidence that key receptor and enzyme components of the endocannabinoid system have distinct subcellular distribution, both intracellularly and extracellularly on presynaptic and postsynaptic neurons, microglia and astrocytes. CB2Rs are mainly expressed following brain injury200. Question marks indicate as yet unknown roles and compartmentalization of ABHD12. AIT, AEA intracellular transporter; EMT, putative endocannabinoid transmembrane transporter; ER, endoplasmic reticulum; TRKs, tyrosine receptor kinases.

  2. Molecular architecture of endocannabinoid signalling during corticogenesis, including neurogenesis and neuronal migration.
    Figure 2: Molecular architecture of endocannabinoid signalling during corticogenesis, including neurogenesis and neuronal migration.

    a | During mid or late gestation in rodents, 2-arachidonoylglycerol (2-AG)-rich cortical microdomains are thought to repulse postmitotic neurons that express cannabinoid 1 receptors (CB1Rs), including radially migrating pyramidal cells and tangentially migrating GABA interneurons in the cerebral cortex. sn-1-diacylglycerol lipase (DAGL) expression in the foetal ventricular proliferative zone and in the cortical plate can produce physiologically relevant extracellular 2-AG concentrations (pink shading). This molecular arrangement, which produces 'corridors' sparse in 2-AG (white areas), could explain some features of the spatially segregated radial migration of pyramidal cells and tangential migration of interneurons. Radial glia function as scaffolds for migrating neurons and can synthesize and subsequently degrade endocannabinoids, thus promoting endocannabinoid-mediated radial detachment of neurons for final positioning. b | At embryonic day 14.5 (E14.5), cannabinoid 1 receptor (CB1R) mRNA is predominantly expressed by neurons in the cortical plate (CP) and hippocampal primordium (hc). Arrows denote CB1R mRNA expression in what are probably interneurons that leave the ganglionic eminence (ge) and migrate towards the cerebral cortex65. c | In mid-gestational mouse brain, DAGLα is expressed at high levels in pyramidal cells and targeted to their axons. GFP-labelled GABAergic interneurons203 can also be seen migrating in the superficial migratory stream (sms) and deep migratory stream (dms). Yellow colour shows the tight spatial arrangement of DAGL-expressing neuronal structures around GFP-labelled GABAergic interneurons, although the GFP-positive cells lacks appreciable DAGL expression. d | CB1R mRNA expression concentrates in the CP and proliferative germinal layers (ne)36, 46 in the human foetal brain (second trimester). Figure part b is modified, with permission, from Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning. Proc. Natl. Acad. Sci. USA 105, 87608765 © (2008) Proc. Natl Acad. Sci. USA. Figure part c is courtesy of T. H. and E. Keimpema, Karolinska Institutet, Sweden. Figure part d is courtesy of Y. L. Hurd, Icahn School of Medicine at Mount Sinai, New York, USA. FAAH, fatty acid amide hydrolase; IZ, intermediate zone; MAGL, monoacylglycerol lipase; MZ; marginal zone; LV, lateral ventricle; SMS, superficial migratory streams; spt, septum; SVZ, subventricular zone; VZ, ventricular zone.

  3. Design logic of endocannabinoid signalling during neurite outgrowth and synaptogenesis.
    Figure 3: Design logic of endocannabinoid signalling during neurite outgrowth and synaptogenesis.

    a | Signal transduction mechanisms implicated in the cannabinoid 1 receptor (CB1R)-mediated control of cortical neuron specification and morphological differentiation are shown. Activation of tyrosine kinase receptors (particularly the fibroblast growth factor receptor (FGFR) and the high-affinity nerve growth factor (NGF) receptor TRKA) and their activity-dependent phosphorylation are thought to induce 2-arachidonoylglycerol (2-AG) production via sequential activation of phospholipase Cγ (PLCγ), which produces diacylglycerol (DAG). DAG is then converted to 2-AG by sn-1-diacylglycerol lipase-α (DAGLα). The dashed arrow in the plasma membrane indicates lateral 2-AG diffusion that can activate CB1Rs in an autocrine manner. Signalling via G proteins recruited to CB1Rs following agonist binding regulates neuronal morphology by, for example, the phosphorylation of JUN N-terminal kinases (JNKs; for example, JNK1)38, which triggers the rapid degradation of stathmin 2 to alter cytoskeletal stability. Alternatively, CB1R activation can modulate the activity of RHO-family GTPases, particularly RHOA, to induce growth cone repulsion and collapse21, 31. Neurotrophins and 2-AG signalling can coincidently activate phosphatidylinositol 3-kinase (PI3K)–AKT signalling. This, in turn, influences the activity of the transcriptional regulators PAX6 and cyclic AMP response element-binding protein (CREB) and their control of neural progenitor cell proliferation and fate decisions (reviewed in Ref. 86). Cytoplasmic breast cancer-associated protein 1 (BRCA1; which is activated by PI3K signalling) is one of the candidate E3 ubiquitin ligases controlling monoacylglycerol lipase (MAGL) degradation68, 86. b | The left-hand panel shows the spatial segregation of molecular determinants of 2-AG signalling during the corticothalamic-thalamocortical axonal 'handshake'. Corticofugal axons are CB1R positive (stained red), whereas thalamocortical axons are CB1R negative but MAGL positive (stained green)48. The right-hand panel shows that corticofugal axons express DAGLs51 and can use paracrine 2-AG signalling for fasciculation (step 1). In turn, autocrine 2-AG signalling in corticofugal axons might be sufficient to promote their elongation (step 2). This molecular layout is compatible with MAGL-positive thalamocortical axons limiting the spatial spread of 2-AG (step 3; the dashed line indicates 2-AG inactivation), thus controlling the distribution of corticofugal fascicles and confining their growth trajectories to a subpallial corridor. Accordingly, pharmacological inhibition of MAGL activity during corticogenesis disrupts the formation of the corticofugal projection system201. c | The subcellular switch of DAGL and MAGL during neuronal polarization and synaptogenesis is shown. In immature neurons, DAGLα is localized to the primary neurite (quiescent axon) and the growth cone, and is probably involved in autocrine signalling. However, once synapses are formed, DAGLα expression is excluded from more proximal parts of the axon and is redistributed to the somatodendritic axis of neurons. By contrast, MAGL becomes enriched at the presynapse, where it probably functions as a 'stop' signal to limit 2-AG-mediated neurite elongation48. The precisely timed molecular reconfiguration of 2-AG signalling supports a continuum of endocannabinoid actions during neuronal differentiation, leading up to the retrograde control of synaptic neurotransmission (inset). DAGLα is selectively enriched in the perisynaptic annulus of dendritic spines (pink shading) apposing glutamatergic afferents49, 202. cfa, corticofugal axon; ctx, cerebral cortex; f, fimbria; hc, hippocampus; lv, lateral ventricle; PIP2, phosphatidylinositol 4,5-bisphosphate; tca, thalamocortical axon; th, thalamus. Figure Part b, left-hand panel, reproduced with permission, and right-hand panel, adapted with permission, Society for Neuroscience.

  4. Defective development of the corticofugal system following genetic manipulation of CB1Rs.
    Figure 4: Defective development of the corticofugal system following genetic manipulation of CB1Rs.

    Conditional deletion204 of cannabinoid 1 receptors (CB1Rs) from mouse cortical pyramidal cells results in errant corticofugal axon fasciculation compared with wild-type controls (shown by arrows). Note that enlarged axon fascicles (encircled) were also seen in extracortical areas, such as the striatum (cpu), where local CB1R expression was unaffected. L1NCAM, L1 neural cell adhesion molecule. Image is reproduced, with permission, from Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning. Proc. Natl. Acad. Sci. USA 105, 87608765 © (2008) Proc. Natl Acad. Sci. USA.

  5. Dysregulation of cannabinoid receptor signalling in glioma cells.
    Figure 5: Dysregulation of cannabinoid receptor signalling in glioma cells.

    a | In neural progenitor cells, endocannabinoid (eCB) binding to cannabinoid receptors couples to the phosphatidylinositol 3-kinase (PI3K)–AKT–mammalian target of rapamycin complex 1 (mTORC1) pathway via Gi proteins. Receptor tyrosine kinases that have been transactivated (by phosphorylation) might amplify cannabinoid receptor-mediated signalling by also using PI3K and RAS as molecular effectors. Activated AKT can elicit cell growth and survival effects (that is, it is mitogenic) either by inhibiting glycogen synthase kinase 3β (GSK3β) and activating β-catenin205 or by activating mTORC1, which leads to p27 inhibition102 as well as PAX6 phosphorylation86 and upregulation of PAX6 expression87. b | In glioma cells, eCBs trigger endoplasmic reticulum (ER) stress by engaging (at least) two mechanisms: binding of eCBs to cannabinoid receptors stimulates de novo synthesis of ceramide in the ER via Gi-dependent and perhaps also via Gi-independent mechanisms179, 180; and binding of eCBs to transient receptor potential cation channel subfamily V member 1 (TRPV1) receptors on the ER mediates Ca2+ release from this organelle to the cytoplasm and, conceivably, depletes ER Ca2+ stores75. Ceramide accumulation and Ca2+ depletion in the ER converge at the phosphorylation (that is, inhibition) of eukaryotic initiation factor 2α (EIF2α) and the induction of activating transcription factor 4 (ATF4), which, in turn, triggers cell death by two signalling cascades: upregulation of tribbles homologue 3 (TRIB3) expression, which leads to the inhibition of the AKT–mTORC1 axis180; and upregulation of ATF3 expression75.


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Author information


  1. School of Medicine and Center of Integrated Research, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, I-00128 Rome, Italy.

    • Mauro Maccarrone
  2. European Center for Brain Research/Santa Lucia Foundation, Via del Fosso di Fiorano 65, I-00143 Rome, Italy.

    • Mauro Maccarrone
  3. Department of Biochemistry and Molecular Biology I and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Complutense University, E-28040 Madrid, Spain.

    • Manuel Guzmán
  4. Department of Psychological and Brain Sciences, Indiana University, 702 N Walnut Grove Avenue, Bloomington, Indiana 47405–2204, USA.

    • Ken Mackie
  5. Wolfson Centre for Age-Related Diseases, King's College, London SE1 1UL, United Kingdom.

    • Patrick Doherty
  6. Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Scheeles väg 1:A1, Karolinska Institutet, SE-17177 Stockholm, Sweden.

    • Tibor Harkany
  7. Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.

    • Tibor Harkany

Competing interests statement

The authors declare no competing interests.

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Author details

  • Mauro Maccarrone

    Mauro Maccarrone was awarded his M.Sc. in biochemistry from the University of L' Aquila, Italy, in 1986, followed by simultaneous Ph.D.s in Enzymology (University of L' Aquila and Tor Vergata University of Rome, Italy) and Bio-organic Chemistry (Utrecht University, The Netherlands) in 1992. He is now Professor and Chair of Biochemistry and Molecular Biology at Campus Bio-Medico University of Rome, Italy. His work focuses on understanding signal transduction induced by endocannabinoids and other arachidonate derivatives and its effects on reproduction and neurodegeneration.

  • Manuel Guzmán

    Manuel Guzmán did his Ph.D. in biology at Madrid Complutense University, Spain. He is now Professor of Biochemistry and Molecular Biology at that university. His laboratory studies how cannabinoid receptors control cell generation and survival, as well as the value of these receptors as therapeutic targets in neurodegeneration and cancer.

  • Ken Mackie

    Ken Mackie carried out his M.D. at Yale University, New Haven, Connecticut, USA, followed by postdoctoral studies with Paul Greengard and Bertil Hille, and an anesthesiology residency at the University of Washington, USA. While at the University of Washington, he began studying ion channel modulation by cannabinoid 1 receptors, showing these receptors inhibit presynaptic calcium channels and activate inwardly rectifying potassium channels. His laboratory studies the pharmacology, signalling, regulation and distribution of cannabinoid receptors, including developmental effects of endogenous and exogenous cannabinoids. He is currently Linda and Jack Gill Professor of Neuroscience at Indiana University, USA.

  • Patrick Doherty

    Patrick Doherty graduated from Strathclyde University in Glasgow, UK, in 1979, and obtained his Ph.D. from the University of London, UK, in 1983. He is currently the Director of the Wolfson Centre for Age-related Diseases at King's College London, UK. His laboratory cloned the diacyglycerol lipases and provided genetic evidence for diacyglycerol-dependent endocannabinoid signalling regulating synaptic plasticity and adult neurogenesis. Current research in his laboratory is focused on the molecular mechanisms regulating diacyglycerol lipase activity.

  • Tibor Harkany

    Tibor Harkany received his M.Sc. from the University of Szeged, Hungary, in 1995, followed by a Ph.D. in medical sciences from Semmelweis University, Hungary. He now jointly holds the positions of Head of the Department of Molecular Neurosciences, Center for Brain Research at the Medical University of Vienna, Austria, and Professor of Neurobiology at the Karolinska Institute, Stockholm, Sweden. His laboratory implicated endocannabinoids in axon guidance and identified molecular substrates of Δ9-tetrahydrocannabinol action in developing neurons. Current research addresses how disrupted endocannabinoid signalling during brain development primes for delayed neuropsychiatric illness.

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