Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex

PLoS One. 2007 Aug 8;2(8):e709. doi: 10.1371/journal.pone.0000709.


Background: Cannabinoids have deleterious effects on prefrontal cortex (PFC)-mediated functions and multiple evidences link the endogenous cannabinoid (endocannabinoid) system, cannabis use and schizophrenia, a disease in which PFC functions are altered. Nonetheless, the molecular composition and the physiological functions of the endocannabinoid system in the PFC are unknown.

Methodology/principal findings: Here, using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers v/vi of the mouse prelimbic area of the PFC: presynaptic cannabinoid CB1 receptors (CB1R) faced postsynaptic mGluR5 while diacylglycerol lipase alpha (DGL-alpha), the enzyme generating the endocannabinoid 2-arachidonoyl-glycerol (2-AG) was expressed in the same dendritic processes as mGluR5. Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents. Prolonged synaptic stimulation at 10Hz induced a profound long-term depression (LTD) of layers V/VI excitatory inputs. The endocannabinoid -LTD was presynaptically expressed and depended on the activation of postsynaptic mGluR5, phospholipase C and a rise in postsynaptic Ca(2+) as predicted from the localization of the different components of the endocannabinoid system. Blocking the degradation of 2-AG (with URB 602) but not of anandamide (with URB 597) converted subthreshold tetanus to LTD-inducing ones. Moreover, inhibiting the synthesis of 2-AG with Tetrahydrolipstatin, blocked endocannabinoid-mediated LTD. All together, our data show that 2-AG mediates LTD at these synapses.

Conclusions/significance: Our data show that the endocannabinoid -retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the PFC. Alterations of endocannabinoid -mediated synaptic plasticity may participate to the etiology of PFC-related pathologies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / metabolism
  • Calcium / metabolism
  • Cannabinoid Receptor Modulators / metabolism*
  • Dopamine Agents / metabolism
  • Endocannabinoids*
  • Glycerides / metabolism
  • Lipoprotein Lipase / antagonists & inhibitors
  • Lipoprotein Lipase / metabolism
  • Long-Term Synaptic Depression / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuronal Plasticity / physiology
  • Patch-Clamp Techniques
  • Prefrontal Cortex / metabolism*
  • Prefrontal Cortex / ultrastructure
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / ultrastructure
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism
  • Schizophrenia / physiopathology
  • Signal Transduction / physiology*
  • Synapses / metabolism
  • Type C Phospholipases / metabolism


  • Arachidonic Acids
  • Cannabinoid Receptor Modulators
  • Dopamine Agents
  • Endocannabinoids
  • Glycerides
  • Grm5 protein, mouse
  • Receptor, Cannabinoid, CB1
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • glyceryl 2-arachidonate
  • Lipoprotein Lipase
  • Type C Phospholipases
  • Calcium