Loss of Retrograde Endocannabinoid Signaling and Reduced Adult Neurogenesis in Diacylglycerol Lipase Knock-out Mice
Open accessAbstract
Endocannabinoids (eCBs) function as retrograde signaling molecules at synapses throughout the brain, regulate axonal growth and guidance during development, and drive adult neurogenesis. There remains a lack of genetic evidence as to the identity of the enzyme(s) responsible for the synthesis of eCBs in the brain. Diacylglycerol lipase-α (DAGLα) and -β (DAGLβ) synthesize 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain. However, their respective contribution to this and to eCB signaling has not been tested. In the present study, we show ∼80% reductions in 2-AG levels in the brain and spinal cord in DAGLα−/−mice and a 50% reduction in the brain in DAGLβ−/−mice. In contrast, DAGLβ plays a more important role than DAGLα in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGLβ−/−mice. Levels of arachidonic acid decrease in parallel with 2-AG, suggesting that DAGL activity controls the steady-state levels of both lipids. In the hippocampus, the postsynaptic release of an eCB results in the transient suppression of GABA-mediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGLα−/−animals and relatively unaffected in DAGLβ−/−animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGLα−/−and/or DAGLβ−/−mice. These findings provide the first evidence that DAGLα is the major biosynthetic enzyme for 2-AG in the nervous system and reveal an essential role for this enzyme in regulating retrograde synaptic plasticity and adult neurogenesis.
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DAGL α and β transform diacylglycerols into 2-AG.
“In contrast, diacylglycerol lipase (DAGL) α and β transform diacylglycerols into 2-AG (Bisogno et al, 2003;Gao et al, 2010;Tanimura et al, 2010).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Gao et al, 2010
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- Authors
- Gao, Y., Vasilyev, D. V., Goncalves, M. B., Howell, F. V., Hobbs, C., Reisenberg, M., Shen, R., Zhang, M.-Y., Strassle, B. W., Lu, P., Mark, L., Piesla, M. J., Deng, K., Kouranova, E. V., Ring, R. H., Whiteside, G. T., Bates, B., Walsh, F. S., Williams, G., Pangalos, M. N., Samad, T. A., & Doherty, P.
- Affiliations
- King's College London (GB)
- Pfizer (United States) (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-02-10
- Volume
- 30
- Issue
- 6
- Pages
- 2017-2024
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6634037
- OpenAlex
- W2035768389
- Cited by
- 473
- References
- 36
- Citations by year
- 2026: 10 · 2025: 23 · 2024: 19 · 2023: 22 · 2022: 26 · 2021: 28 · 2020: 20 · 2019: 16 · 2018: 24 · 2017: 21 · 2016: 33 · 2015: 42 · 2014: 42 · 2013: 37 · 2012: 49
- FWCI
- 34.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- endocannabinoids, diacylglycerol lipase alpha, 2-arachidonoylglycerol, adult neurogenesis, hippocampus, subventricular zone, arachidonic acid, endocannabinoid biosynthesis
- MeSH terms
- Animals, Arachidonic Acids, Brain, Glycerides, Hippocampus, Lipoprotein Lipase, Liver, Neuronal Plasticity, Spinal Cord, Synapses, Signal Transduction, Mice, Knockout, Mice, Neurogenesis, Cannabinoid Receptor Modulators, Endocannabinoids
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