“LTP” is long-term potentiation, a type of synaptic plasticity found in the hippocampus that is involved in episodic memory storage. A recent research article reports on the mechanism by which endocannabinoid signaling affects the induction of hippocampal long-term potentiation (LTP).
The new study concerns the role of presynaptic cannabinoid receptors (CB1R, see the image to the right) that respond to the endogenous cannabinoid 2-arachidonoyl-sn-glycerol (2AG). Two arachidonic acid derivatives, N-arachidonoylethanolamine (anandamide, AEA) and 2AG are the best studied endogenous cannabinoids. Both Δ9-tetrahydrocannabinol (THC), the main psychoactive molecule from cannabis and these two endogenous cannabinoids activate the CB1R.
The endogenous cannabinoid 2AG can be made in dendrites by two enzymes, DGL or phospholipase C (PLC). The new research from the laboratory of Gary Lynch concerns production of LTP in the lateral perforant path (LPP), one of the cortical inputs to the hippocampus. Endogenous cannabinoids such as 2AG play normal roles in brain function and the actions of THC at CB1R are probably involved in the influence of cannabinoid drugs on orderly thought.
One way of activating PLC and 2AG synthesis in dendrites is via the action of glutamate on GluR5, a G protein-coupled receptor (see the diagram at the top right of this blog post). Glutamate is a common neurotransmitter at synapses in the hippocampus. In some parts of the brain, glutamate actions to activate NMDA receptors has been shown to lead to LTP, often via postsynaptic mechanisms involving altered levels of postsynaptic membrane receptors. Lynch et al provide evidence concerning how glutamate actions on GluR5, production of 2AG and activation of presynaptic CB1R can cause another form of LTP.
The image to the right illustrates the proposed presynaptic mechanism of CB1R-mediated LTP at the glutamanergic synapses formed by the LPP with granule cells of the dentate gyrus (DG, an important input region of the hippocampal formation).
In this model, the 2AG synthesizing enzyme diacylglycerol lipase (DGL) requires calcium for activity and is localized to dendritic spines, where it forms a multimolecular complex with mGluR5. In the model, glutamate (green triangles) activates mGluR5 and NMDA receptors leading to increases in postsynaptic calcium levels, activation of DGL and the production of 2AG (pink circles).
The 2AG then binds to presynaptic CB1R triggering a long-lasting increase in glutamate release. Block of actin filament reorganization with latrunculin A inhibited this LTP, suggesting that reorganization of the actin cytoskeleton in LPP axon terminals is involved in facilitating glutamate release during LTP. They propose that activated presynaptic CB1 receptors can promote cytoskeletal reorganization via a signaling cascade that involves a small GTPases (RhoA, Rac or Rap) that can regulate actin polymerization.
Related reading: A cannabinoid link between mitochondria and memory