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
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This paper shows that neural progenitor cells in the subventricular zone of the cerebral cortex express CB2Rs and use an autocrine DAGL–CB2R signalling arrangement to promote neurogenesis.
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This paper reports the generation of DAGL-null mice and provides genetic evidence on the requirement of DAGL function for continued neurogenesis in the mouse forebrain during postnatal life.
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In this paper, the authors identify anandamide as the first endogenous ligand of CB1Rs in the brain. This landmark paper marks the advent of contemporary endocannabinoid research.
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This paper provides the molecular identity and describes the expression sites and signalling mechanisms of cannabinoid receptors and the key metabolic enzymes for endocannabinoids in astroglia. Moreover, it establishes the role of endocannabinoids in cell fate decisions and lineage commitment.
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In this paper, the authors show that axonal CB1Rs can sense extracellular ligand gradients and can induce growth cone repulsion or collapse. This mechanism is then implicated in disrupted synaptogenesis in the cortex of mice lacking CB1Rs in GABAergic cortical interneurons.
- The type 1 cannabinoid receptor is highly expressed in embryonic cortical projection neurons and negatively regulates neurite growth in vitro. Eur. J. Neurosci. 28, 1705–1718 (2008). et al.
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This paper reports that neuronal commitment coincides with the upregulation of CB1R in the earliest-born neurons of the chick embryo. This proposal led to subsequent mechanistic studies implicating CB1R functions in a broad range of developmental processes.
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In this paper, the authors report on foetal growth retardation as a consequence of maternal cannabis smoking. The study is particularly important to show that many organ systems are sensitive to phytocannabinoid disruptors.
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This paper is the first molecular analysis of THC effects on neuronal differentiation, particularly axon guidance. By unbiased proteomics, SCG10 is identified as the first molecular effector of unwanted THC effects on neuronal morphology.
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- Localization of diacylglycerol lipase-α around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor. J. Neurosci. 26, 4740–4751 (2006). et al.
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- Cloning of the first sn-1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J. Cell Biol. 163, 463–468 (2003).
This paper identifies the DAGLs, shows their distribution in both the developing and adult nervous system and suggests a striking switch in DAGL expression sites during synaptogenesis. The substrate and product specificity of DAGL is also defined.
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- Estradiol acutely suppresses inhibition in the hippocampus through a sex-specific endocannabinoid and mGluR-dependent mechanism. Neuron 74, 801–808 (2012). &
- TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. Nature Neurosci. 13, 1511–1518 (2010). , &
- Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens. Nature Neurosci. 13, 1519–1525 (2010). , &
- Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur. J. Neurosci. 20, 441–458 (2004). et al.
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- Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron 34, 787–796 (2002). , &
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- Developmental pattern of CB1 cannabinoid receptor immunoreactivity in brain regions important to zebra finch (Taeniopygia guttata) song learning and control. J. Comp. Neurol. 496, 739–758 (2006). &
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- Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons. Proc. Natl Acad. Sci. USA 110, 1935–1940 (2013). et al.
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- Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. Nature Med. 18, 1232–1238 (2012). et al.
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In this paper, the authors define a minimal transcription factor network downstream from CB1Rs that is required for neurite outgrowth. They also implicate BRCA1 in cannabinoid signalling, which was shown as a candidate to control MAGL stability by Keimpema in 2013.
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- CB1 cannabinoid receptor-dependent activation of mTORC1/PAX6 signaling drives TBR2 expression and basal progenitor expansion in the developing mouse cortex. Cereb. Cortex 7 Mar 2014 [Epub ahead of print]. et al.
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- Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TRKB receptor. Proc. Natl Acad. Sci. USA 102, 19115–19120 (2005). et al.
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- The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response. J. Cell Biol. 160, 481–486 (2003).
In this paper, the authors suggest that endocannabinoid signalling is regulated by FGFRs and that this coupling underpins FGF-induced neurite outgrowth.
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This paper describes the interplay between AEA action at TRPV1 and the metabolic control and CB1R engagement of 2-AG, which allow AEA to control the 'endogenous tone' and physiological action of 2-AG in the striatum.
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This paper describes the distribution of CB1Rs, 2-AG and AEA at successive developmental periods in foetal rodent brains. The authors suggest a temporal association between receptor expression and ligand bioavailability.
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This paper describes the initial characterization of CB1R-null mice, showing their premature death during aging. However, this study failed to identify developmental abnormalities.
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This paper defines transcriptional elements by which cannabinoids can trigger glioma cell death. It also highlights the relevance and the efficacy of phytocannabinoids to cancer therapy.
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