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

Key Points

  • Cannabinoid receptor diversity and signalling in the immature brain are vastly different from those in the adult nervous system. These include the differential localization of, and signal transduction by, cannabinoid receptors and the enzymes that limit endocannabinoid bioavailability. CB1 and CB2 cannabinoid receptors signal neural progenitor proliferation in the developing brain, including gliogenesis, by coupling to mitogenic pathways such as PI3K and ERK.

  • Endocannabinoid hot spots can facilitate the directional migration of postmitotic neurons in the foetal nervous system, as well as of neuroblasts in neurogenic areas of the adult mammalian brain.

  • CB1 cannabinoid receptors, and probably CB2 and TRPV1 receptors, in growth cones signal to modulate steering decisions during directional axonal growth. In part, autocrine signalling by endocannabinoids mediates neurite elongation.

  • Diacylgycerol lipase-dependent endocannabainoid signalling regulates neurogenesis in the adult hippocampus and subventricular zone.

  • Δ9-THC affects neuronal development via CB1 cannabinoid receptor-mediated mechanisms, disrupting cytoskeletal integrity, axonal growth and synaptogenesis. Therefore, THC exposure is adverse in developmental contexts.

  • Preclinical evidence suggests that pharmacological activation of cannabinoid receptors might be exploited therapeutically to inhibit tumor growth in glioma patients.


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.

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Figure 1: Molecular architecture of the endocannabinoid system during synaptogenesis and at mature synapses.
Figure 2: Molecular architecture of endocannabinoid signalling during corticogenesis, including neurogenesis and neuronal migration.
Figure 3: Design logic of endocannabinoid signalling during neurite outgrowth and synaptogenesis.
Figure 4: Defective development of the corticofugal system following genetic manipulation of CB1Rs.
Figure 5: Dysregulation of cannabinoid receptor signalling in glioma cells.


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This work was supported by the Ministero dell'Istruzione, dell'Università e della Ricerca (PRIN 2010–2011 grant to M.M.), Swedish Medical Research Council (to T.H.), Novo Nordisk Foundation (to T.H.), Petrus and Augusta Hedlunds' Foundation (to T.H.), the Wellcome Trust (to P.D.), the Spanish Ministry of Economy and Competitiveness (grant SAF201235759 to M.G.), the European Commission (FP7 'PAINCAGE' integrated project to T.H.) and the National Institutes of Health (grant DA023214 to T.H., and grants DA011322 and DA021696 to K.M.). The content of this report is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. M.M. dedicates this Review to his late father, Giuseppe.

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Correspondence to Mauro Maccarrone or Tibor Harkany.

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The authors declare no competing financial interests.

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Morphogenetic signals

Gradients of molecules that determine the position of specialized cellular subtypes and instruct their communication and functional role during histogenesis.


Molecules that contain the organic aliphatic amino alcohol sphingosine or a structurally similar molecule as a backbone.


Endogenous compounds that bind to cannabinoid 1 receptors (CB1Rs) and/or CB2Rs with high affinity, and are able to evoke a Δ9-tetrahydrocannabinol-like behavioural tetrad.

sn-1-diacylglycerol lipase-α

(DAGLα). Two isoforms of DAGL, DAGLα and DAGLβ, which probably evolved evolutionarily through gene duplication, are chiefly responsible for 2-AG synthesis.

Tripartite synapse

A concept of synaptic anatomy that includes the presynaptic terminal, postsynaptic specialization and astroglial end-feet that isolate the synaptic cleft as a discrete entity.

Subventricular zone

A progenitor cell-rich part of the cerebral cortex that lines the dorsolateral surface of the lateral ventricle and retains neurogenic capacity throughout life.

Corticothalamic–thalamocortical handshake

Where corticothalamic and thalamocortical axons with opposite growth trajectories cross one another.

Cytoskeletal instability

The dynamic reorganization of the cytoskeleton by differentially altering the elongation and shortening of the '+' and '−' ends of mictotubules.


The process by which developing axons follow a primary pioneer axon, thus maintaining strict directionality towards a distal target.


A postmitotic cell in an undifferentiated form migrating towards its final position, where it becomes a neuron.

Functional antagonist

A drug that is pharmacologically classified as an agonist; it induces a phenotype similar to that provoked by an antagonist, often by downregulation of signalling.

Psychoactive component

The molecular component of a plant extract that can provoke acute changes in perception of behaviour.


A molecule that consists of sphingosine and a fatty acyl chain; it is therefore one of the structurally simplest forms of sphingolipids.

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Maccarrone, M., Guzmán, M., Mackie, K. et al. Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat Rev Neurosci 15, 786–801 (2014).

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