The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission

Neuron. 2010 Feb 11;65(3):320-7. doi: 10.1016/j.neuron.2010.01.021.

Abstract

Endocannabinoids are released from postsynaptic neurons and cause retrograde suppression of synaptic transmission. Anandamide and 2-arachidonoylglycerol (2-AG) are regarded as two major endocannabinoids. To determine to what extent 2-AG contributes to retrograde signaling, we generated and analyzed mutant mice lacking either of the two 2-AG synthesizing enzymes diacylglycerol lipase alpha (DGLalpha) and beta (DGLbeta). We found that endocannabinoid-mediated retrograde synaptic suppression was totally absent in the cerebellum, hippocampus, and striatum of DGLalpha knockout mice, whereas the retrograde suppression was intact in DGLbeta knockout brains. The basal 2-AG content was markedly reduced and stimulus-induced elevation of 2-AG was absent in DGLalpha knockout brains, whereas the 2-AG content was normal in DGLbeta knockout brains. Morphology of the brain and expression of molecules required for 2-AG production other than DGLs were normal in the two knockout mice. We conclude that 2-AG produced by DGLalpha, but not by DGLbeta, mediates retrograde suppression at central synapses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Arachidonic Acids / metabolism*
  • Calcium / metabolism
  • Cells, Cultured
  • Cerebellum / cytology
  • Cerebellum / drug effects
  • Cerebellum / physiology
  • Corpus Striatum / cytology
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiology
  • Electric Stimulation / methods
  • Endocannabinoids
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Gene Expression Regulation / genetics
  • Glycerol / analogs & derivatives*
  • Glycerol / metabolism
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / genetics
  • Lipoprotein Lipase / classification
  • Lipoprotein Lipase / deficiency
  • Lipoprotein Lipase / metabolism*
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Inhibition / drug effects
  • Neural Inhibition / genetics
  • Neural Inhibition / physiology*
  • Neurons / drug effects
  • Neurons / physiology
  • Patch-Clamp Techniques / methods
  • Polyunsaturated Alkamides / metabolism
  • Potassium Chloride / pharmacology
  • Statistics, Nonparametric
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics
  • Synaptic Transmission / physiology*

Substances

  • Arachidonic Acids
  • Endocannabinoids
  • Polyunsaturated Alkamides
  • Methoxyhydroxyphenylglycol
  • Potassium Chloride
  • Lipoprotein Lipase
  • Glycerol
  • Calcium
  • 3,4-dihydroxyphenylglycol
  • anandamide