Endocannabinoids at the synapse a decade after the dies mirabilis (29 March 2001): what we still do not know

Abstract

Endogenous cannabinoids (endocannabinoids, eCBs) are ubiquitous regulators of synaptic transmission in the brain, mediating numerous forms of short- and long-term plasticity, and having strong influences on synapse formation and neurogenesis. Their roles as retrograde messengers that suppress both excitatory and inhibitory transmission are well-established. Yet, despite intensive investigation, many basic aspects of the eCB system are not understood. This brief review highlights recent advances, problems that remain unresolved, and avenues for future exploration. While 2-arachidonoylglycerol (2-AG) is probably the major eCB for intercellular CB1R-dependent signalling, anandamide (AEA) has come to the forefront in several novel contexts, both as a dual endovanilloid/endocannabinoid that regulates synaptic transmission acutely and as the source of a steady eCB tone in hippocampus. Complexities in the cellular processing of 2-AG are receiving renewed attention, as they are increasingly recognized as major determinants of how 2-AG affects cells. Long-standing fundamental issues such as the synthesis pathway for AEA and the molecular mechanism(s) underlying cellular uptake and release of eCBs remain problematical.

Figure 1. New roles for anandamide (AEA)

A, model showing postsynaptic generation of AEA by mGluR5 activation in D2 receptor expressing (D2+) medium spiny neurons (MSNs) in the nucleus accumbens. AEA then induces a postsynaptic form of LTD by activating postsynaptic TRPV1 channels and triggering dynamin-dependent endocytosis of AMPARs. AEA is also released as a retrograde messenger and activates CB1Rs on presynaptic glutamatergic terminals onto the MSNs. The CB1R-mediated effect leads to a presynaptic, RIM1α-dependent form of LTD, by persistently suppressing glutamate release. B, tonic suppression of GABA release from CB1R-expressing interneurons in hippocampus represents a homeostatic activity-dependent mechanism. In these cells AEA is normally released in a steady manner that is dependent on the basal, not stimulated, level of [Ca²⁺]_i (top). Chronic inactivity of the system leads to an upregulation in the activity of uptake and degradation mechanisms, thus lowering the amount of AEA available to activate CB1R. A from Grueter et al. (2010) with permission from Nature Publishing Group. B from Kim & Alger (2010) with permission.