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


RESULTS
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
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.
INSERM U862, Equipe Physiopathologie de la plasticité synaptique, Bordeaux, France.
Mathieu
M
Lafourcade
Izaskun
I
Elezgarai
Susana
S
Mato
Yamina
Y
Bakiri
Pedro
P
Grandes
Olivier J
OJ
Manzoni
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D015259:Dopamine Agents / Q000378:metabolism; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000502:physiology; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000648:ultrastructure; D017966:Pyramidal Cells / Q000378:metabolism / Q000648:ultrastructure; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism; D012559:Schizophrenia / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D015259:Dopamine Agents; D063388:Endocannabinoids; D005989:Glycerides; C578936:Grm5 protein, mouse; D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C094503:glyceryl 2-arachidonate; D008071:Lipoprotein Lipase; D010738:Type C Phospholipases; D002118:Calcium