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Review
. 2012 May 15;590(10):2203-12.
doi: 10.1113/jphysiol.2011.220855. Epub 2012 Jan 30.

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

Bradley E Alger  1
Affiliations
Review

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

Bradley E Alger. J Physiol. .

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.

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Figures

Figure 1
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.
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