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Endocannabinoids: Going retro with DAGLα


Nature Reviews Neuroscience 11, 224-225, (April 2010)
[doi:10.1038/nrn2824]

One of the main endocannabinoids (eCBs) in the CNS is 2-arachidonoylglycerol (2-AG), which can be synthesized from diacylglycerol by diacylglycerol lipase-α (DAGLα) and DAGLβ. The extent to which these two enzymes contribute to 2-AG synthesis in the brain was unknown, but two recent papers show that DAGLα is essential for 2-AG synthesis and endocannabinoid signalling in the brain.

Gao et al. and Tanimura et al. investigated mice lacking either DAGLα or DAGLβ. Gao et al. showed that 2-AG levels in the brain and spinal cord of adult DAGLα−/− mice were reduced by 80%, whereas DAGLβ−/− mice had 50% less 2-AG in the brain only. Arachidonic acid levels decreased in parallel with 2-AG, suggesting that the DAGL enzymes are also responsible for producing this essential lipid. Tanimura et al. also measured greatly reduced 2-AG levels in the cerebellum, hippocampus and striatum of DAGLα−/− mice but detected no change in DAGLβ−/− mice.

2-AG functions as a retrograde signalling molecule, suppressing synaptic transmission at central synapses; both groups assessed whether the absence of DAGLα or DAGLβ affected this process. Tanimura et al. used three protocols that are known to trigger endocannabinoid release — depolarization of postsynaptic neurons, activation of Gq/11-coupled receptors, and simultaneous Ca2+ elevation and activation of Gq/11-coupled receptors. As expected, in cerebellar slices of wild-type mice, each of these methods resulted in suppression of synaptic transmission at both excitatory and inhibitory synapses. Cultured hippocampal neurons, hippocampal slices and striatal slices of wild-type mice showed similar endocannabinoid-mediated suppression of synaptic transmission. Crucially, these responses did not occur in cells or slices taken from DAGLα−/− mice, but were intact in DAGLβ−/− mice. The expression of other molecules involved in endocannabinoid signalling, including phospholipase Cβ4 and cannabinoid receptor 1, were normal in the knockout mice. Similarly, Gao et al. showed suppression of evoked inhibitory postsynaptic currents in response to depolarization-induced endocannabinoid release in hippocampal slices of wild-type and DAGLβ−/− mice, but not in slices taken from DAGLα−/− mice. Taken together, these findings indicate that 2-AG produced by DAGLα is essential for mediating retrograde synaptic suppression.

There is some evidence that cannabinoid receptor signalling has a role in regulating adult neurogenesis. Gao et al. used bromodeoxyuridine to label proliferating cells in two neurogenic areas — the subventricular zone (SVZ) and the hippocampus — of wild-type and knockout mice. The numbers of proliferating cells in the SVZ and the hippocampus of mice lacking DAGLα were reduced by 50% and 20%, respectively. DAGLβ−/− mice had similar levels of proliferating cells to wild-type mice in the SVZ, but reduced neurogenesis in the hippocampus.

Interestingly, in both studies the knockout mice were behaviourally indistinguishable from wild-type mice, and their brains showed no overall abnormalities. Thus, although DAGLα may not be required for normal brain development, these two papers showed that it is essential for the synthesis of 2-AG in the brain and for the role of this endocannabinoid in retrograde signalling and adult neurogenesis.

Leonie Welberg

- Copyright © 2010 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission

References:

ORIGINAL RESEARCH PAPERS

  1. Gao, Y. et al. Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice.

    J. Neurosci. 30, 2017-2024 (2010).

  2. Tanimura, A. et al. The endocannabinoid 2-arachidonoyl-glycerol produced by diacylglycerol lipase α mediates retrograde suppression of synaptic transmission.

    Neuron 65, 320-327 (2010).

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