Molecular Components and Functions of the Endocannabinoid System in Mouse Prefrontal Cortex

Abstract

BackgroundCannabinoids 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 FindingsHere, 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 α (DGL-α), 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 Ca2+ 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/SignificanceOur 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.

Cannabinoids and Epilepsy

“…CB 1 Rs are most densely expressed at cortical and hippocampal presynaptic γ-aminobutyric acid (GABA)ergic presynaptic boutons, especially cholecystokinin-positive (CCK+) and parvalbumin-negative GABAergic interneurons [64][65][66]. Glutamatergic axon terminals in cortical and subcortical neurons contain fewer presynaptic CB1 receptors than GABAergic terminals [65,[67][68][69][70][71].…”

Endocannabinoids via CB1receptors act as neurogenic niche cues during cortical development

“…At these stages, the CB 1 receptor is also present in the subpial area of the ganglionic eminences and the primordium of the hippocampus [15]. Later, CB 1 receptors are heterogeneously distributed through cortical layers and the hippocampus, in both excitatory glutamatergic projection neurons, as identified by vGlut1 expression, and cholecystokinin (CCK)-expressing GABAergic interneurons colabelled with vGlut3 [16][17][18]. CB 1 þ CCK þ interneurons derived from the ganglionic eminences follow tangential migratory routes from the ventral telencephalon and reach the developing cortex, hippocampus and amygdala [15,[19][20][21].…”

The evolution and comparative neurobiology of endocannabinoid signalling

“…For example, stimulation of cortical glutamatergic input to the striatum causes activation of postsynaptic metabotropic glutamate receptors, leading to endocannabinoid/ CB 1 -mediated LTD of transmission at excitatory cortico-striatal synapses [67]. Endocannabinoid/CB 1 -mediated LTD has subsequently been reported in other brain regions and there is evidence that, as with DSE and DSI, it is postsynaptic formation of 2-AG that mediates this particular form of long-term synaptic plasticity [68].…”