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- Title
Loss of Retrograde Endocannabinoid Signaling and Reduced Adult Neurogenesis in Diacylglycerol Lipase Knock-out Mice.
- Authors
Ying Gao; Vasilyev, Dmitry V.; Goncalves, Maria Beatriz; Howell, Fiona V.; Hobbs, Carl; Reisenberg, Melina; Ru Shen; Mei-Yi Zhang; Strassle, Brian W.; Peimin Lu; Mark, Lilly; Piesla, Michael J.; Kangwen Deng; Kouranova, Evguenia V.; Ring, Robert H.; Whiteside, Garth T.; Bates, Brian; Walsh, Frank S.; Williams, Gareth; Pangalos, Menelas N.
- Abstract
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 (DAGLα) 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 DAGLβ-/- mice and a 50% reduction in the brain in DAGLβ-/- mice. In contrast, DAGLβ plays a more important role than DAGLβ 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 GABAmediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGLβ-/- 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 DAGLβ-/-and/or DAGLβ-/- mice. These findings provide the first evidence that DAGLβ 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.
- Subjects
DEVELOPMENTAL neurobiology; DIGLYCERIDES; LIPASES; LABORATORY mice; NEURAL development; MOLECULES
- Publication
Journal of Neuroscience, 2010, Vol 30, Issue 6, p2017
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5693-09.2010