Endocannabinoids and their implications for epilepsy

Abstract

This review covers the main features of a newly discovered intercellular signaling system in which endogenous ligands of the brain's cannabinoid receptors, or endocannabinoids, serve as retrograde messengers that enable a cell to control the strength of its own synaptic inputs. Endocannabinoids are released by bursts of action potentials, including events resembling interictal spikes, and probably by seizures as well. Activation of cannabinoid receptors has been implicated in neuroprotection against excitotoxicity and can help explain the anticonvulsant properties of cannabinoids that have been known since antiquity.

Figure 1

Summary of endocannabinoid synthesis and actions. Endocannabinoids are synthesized from membrane phospholipids in the postsynaptic cell via at least two distinct pathways in postsynaptic (Post) principal cells: a calcium-dependent pathway and a pathway that is independent of calcium but dependent on the activation of G proteins. The calcium-dependent release is caused by entry of calcium into the cell through voltage-gated calcium channels. G protein–dependent synthesis is set into motion by activation of either a muscarinic acetylcholine receptor (mAChR) or a metabotropic glutamate receptor (mGluR). These G protein pathways are independent at the receptor level and probably interact in some way that is not yet fully defined. In addition, the G protein activation can enhance the synthesis and release of endocannabinoids via calcium. Once released, either via diffusion through the postsynaptic cell membrane or by transport out of the cell, the endocannabinoids gain access to the CB1 cannabinoid receptors that are located on the nerve terminals of either GABAergic interneurons (e.g., in hippocampus, neocortex, and amygdala) or on excitatory glutamatergic axons (e.g., cerebellum). The calcium-dependent pathway produces depolarization-induced suppression of inhibition (DSI) or DSE, depending on whether the target CB1 receptors are located on inhibitory or excitatory nerve terminals. (Figure prepared with the assistance of Dr. J. Kim.)