Molecular Composition of the Endocannabinoid System at Glutamatergic Synapses

Abstract

Endocannabinoids play central roles in retrograde signaling at a wide variety of synapses throughout the CNS. Although several molecular components of the endocannabinoid system have been identified recently, their precise location and contribution to retrograde synaptic signaling is essentially unknown. Here we show, by using two independent riboprobes, that principal cell populations of the hippocampus express high levels of diacylglycerol lipase ␣ (DGL-␣), the enzyme involved in generation of the endocannabinoid 2-arachidonoyl-glycerol (2-AG). Immunostaining with two independent antibodies against DGL-␣ revealed that this lipase was concentrated in heads of dendritic spines throughout the hippocampal formation. Furthermore, quantification of high-resolution immunoelectron microscopic data showed that this enzyme was highly compartmentalized into a wide perisynaptic annulus around the postsynaptic density of axospinous contacts but did not occur intrasynaptically. On the opposite side of the synapse, the axon terminals forming these excitatory contacts were found to be equipped with presynaptic CB 1 cannabinoid receptors. This precise anatomical positioning suggests that 2-AG produced by DGL-␣ on spine heads may be involved in retrograde synaptic signaling at glutamatergic synapses, whereas CB 1 receptors located on the afferent terminals are in an ideal position to bind 2-AG and thereby adjust presynaptic glutamate release as a function of postsynaptic activity. We propose that this molecular composition of the endocannabinoid system may be a general feature of most glutamatergic synapses throughout the brain and may contribute to homosynaptic plasticity of excitatory synapses and to heterosynaptic plasticity between excitatory and inhibitory contacts.

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].…”

A neuroscientist's guide to lipidomics

“…4). Type I mGluR, PLC-β and DGL-α are localized at the perisynapse (light red), a region of the dendritic spine that borders the postsynaptic density (purple) [63][64][65][66] . 2-AG crosses the synaptic cleft and activates presynaptic CB 1 cannabinoid receptors (CB 1 R), which suppress glutamate release.…”

“…Immunogold electron-microscopy studies of hippocampal and cerebellar neurons have shown that this lipid hydrolase is primarily localized in a subdivision of the dendritic spine, called the perisynapse, which forms a thin border (100-200 nm thick) around the postsynaptic density 63,64 . Along with DAG lipase α, this same area also contains type I mGlurs 65 and phospholipase C-β 66 , and might, thus, be viewed as a stable perisynaptic site for the receptor-operated release of 2-AG.…”

“…Facing DGlα, on the opposite side of the synaptic cleft, are both CB 1 rs 63 and monoacylglycerol lipase 67 , a presynaptic enzyme that cleaves 2-AG to terminate its actions 32,61,68 . We do not know precisely how 2-AG crosses the water-filled cleft to reach CB 1 r-containing terminals, but its amphipathic nature and/or its association with extracellular lipid-binding proteins 69,70 are likely to be important.…”