Review
Retrograde signaling by endocannabinoids

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Abstract

Recent studies suggest that endocannabinoids act as retrograde messengers at many synapses in the central nervous system. Activation of phospholipases, either through calcium-mediated or receptor-mediated signaling, leads to the formation and release of endocannabinoids. These lipophilic signaling molecules diffuse to nearby presynaptic terminals where they bind to specific G-protein-coupled receptors and inhibit neurotransmitter release for tens of seconds. Thus, an important physiological role of endocannabinoids may be to provide a mechanism by which neurons can rapidly regulate the strength of their synaptic inputs.

Introduction

Although the psychoactive properties of the marijuana plant, Cannabis sativa, have been known for thousands of years, the existence of receptors that bind the active compound, Δ9-tetrahydrocannabinol, has only recently been documented 1., 2.. This discovery suggested the presence of an endogenous signaling system that could utilize these widely expressed receptors. Subsequently, several arachidonic acid derivatives that activate the cannabinoid receptor were isolated, including arachidonylethanolamide (anandamide) [3] and 2-arachidonylglycerol (2-AG) 4., 5.. The formation of these endogenous cannabinoids, or endocannabinoids, is stimulated by calcium 6., 7. and mechanisms have been proposed for their transport and enzymatic degradation 8., 9., 10.. Although these reports firmly established the existence of an endocannabinoid signaling system, its functional role in the brain was not well understood.

As the endocannabinoid system was being discovered, parallel studies revealed a phenomenon known as depolarization-induced suppression of inhibition (DSI) 11., 12., 13.. DSI has been studied in the cerebellum and the hippocampus, although it is likely present in other brain regions as well. It occurs following depolarization of a postsynaptic neuron and is characterized by a transient presynaptic suppression of inhibitory postsynaptic currents (IPSCs). Initial reports indicated that DSI is triggered in response to a rise in postsynaptic calcium levels and involves a retrograde messenger released by the postsynaptic cell 11., 12., 14., 15.. However, until last year, despite extensive characterization of DSI in the cerebellum and hippocampus, several outstanding issues remained. It was not known whether DSI was restricted to inhibitory synapses in the hippocampus and cerebellum or whether it represented a more general type of synaptic regulation. In addition, the identity of the retrograde messenger and its mechanism of action had not been determined.

Recent studies indicate that endocannabinoids mediate the rapid retrograde suppression of both excitatory and inhibitory synapses 16••., 17••., 18••.. Here, we briefly overview the endocannabinoid system (for more extensive reviews, see 19., 20., 21., 22., 23., 24.). We then focus on recent studies in the hippocampus and cerebellum that highlight a role for retrograde signaling by endocannabinoids in the central nervous system.

Section snippets

The cannabinoid receptor

Most physiological effects of cannabinoids are mediated through specific receptors. Initial characterization of the cannabinoid receptor [1] and its distribution in vertebrate brain [25] utilized a high-affinity radiolabeled cannabinoid agonist. The highest levels of cannabinoid binding were found in the basal ganglia, cerebellum, hippocampus, and cortex. The receptor, which was cloned and identified as a seven-transmembrane domain G-protein-coupled receptor [2], is prominently expressed in the

Retrograde signaling by endocannabinoids

Recent studies have resolved many issues regarding retrograde synaptic inhibition and the role of cannabinoid signaling in the brain. In addition to suppressing inhibitory synapses, postsynaptic depolarization can modulate excitatory synapses, through a process known as depolarization-induced suppression of excitation (DSE) [18••]. Furthermore, experiments have established that endocannabinoids are the retrograde messengers for DSI in the hippocampus 16••., 17••. (Fig. 2b) and for both DSI and

Mechanisms of synaptic inhibition by cannabinoids

The primary mechanism by which endocannabinoids suppress synaptic inputs is though CB1 receptor-mediated activation and G-protein-mediated inhibition of presynaptic calcium channels. This has been demonstrated at the climbing fiber to Purkinje cell synapse during DSE, by imaging presynaptic calcium influx evoked by an action potential [18••]. Purkinje cell depolarization decreased calcium entry with a time course similar to that of excitatory postsynaptic current (EPSC) suppression, and this

Physiological significance

Although depolarization of voltage-clamped neurons provides a simple protocol to elicit calcium influx and endocannabinoid formation, it is also important to consider what types of stimuli give rise to DSI and DSE under more realistic conditions. In the hippocampus, repetitive firing (20 Hz, 2 s) in CA1 pyramidal cells elicits DSI [12], and repetitive stimulation (50 Hz, 3–5 s) of synaptic inputs onto cells in hippocampal cultures also results in suppression of GABA release [17••]. In the

Conclusions and future directions

Endocannabinoids are lipophilic signaling molecules, which are synthesized de novo from membrane phospholipids in response to postsynaptic depolarization or mGluR activation. They can diffuse to nearby presynaptic terminals where they suppress neurotransmitter release by inhibiting calcium channels. The timecourse of endocannabinoid modulation is longer than the ∼1 s inhibition produced by local GABA release [71] and much more rapid than activity-dependent synaptic scaling, which requires hours

Update

A recent study in the cerebellum has confirmed that DSI is mediated by endocannabinoids [73]. This study found that cerebellar DSI — similarly to previous results concerning hippocampal DSI — requires CB1 receptors, because DSI is absent in CB1 knockout mice, [54•]. Another study in the hippocampus found that endocannabinoid release following depolarization is enhanced nonlinearly in the presence of a postsynaptic mGluR agonist, suggesting that multiple signaling pathways may converge to

Acknowledgments

We thank Dawn Blitz, Stephan Brenowitz, Solange Brown, Adam Carter, Kelly Foster, Patrick Safo, and Matthew Xu-Friedman for comments on the manuscript.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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