Endocannabinoid Signaling and Synaptic Function

Abstract

Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a non-retrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. Synaptic endocannabinoid signaling is thus mechanistically more complex and diverse than originally thought. In this review, we focus on new advances in endocannabinoid signaling and highlight their role as potent regulators of synaptic function in the mammalian brain.

Endocannabinoid-mediated retrograde modulation of synaptic transmission

“…Here we show the standard 2-AG model ( Fig. 1), which can explain most, if not all, results of electrophysiological studies [1][2][3][4][5]. The conditions that induce the production and release of 2-AG are mechanistically classified into three types; increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) (Ca 2+ -driven endocannabinoid release, CaER), activation of G q/11 -coupled receptors (basal receptor-driven endocannabinoid release, basal RER), and the combination of these two (Ca 2+ -assisted RER) [1,2,6].…”

“…eCB-LTD is induced mostly by repetitive afferent stimulation with or without postsynaptic depolarization, but also by postsynaptic firing [1,4,22,23]. Most types of eCB-LTD are mediated by 2-AG.…”

“…Endocannabinoids retrogradely modulate synaptic transmission widely throughout the central nervous system [1][2][3][4][5]. They are released from postsynaptic neurons, activate presynaptic CB 1 cannabinoid receptors, and suppress transmitter release either transiently (endocannabinoid-mediated short-term depression; eCB-STD) or persistently (endocannabinoid-mediated long-term depression; eCB-LTD).…”

“…The ability of each synapse to express eCB-STD/LTD depends primarily on whether the presynaptic terminal expresses CB 1 receptors. In addition to their well-established functions as retrograde messengers, endocannabinoids might also function in non-retrograde manners [4]. In the last few years evidence has also accumulated to suggest that the endocannabinoid signaling system itself is regulated by various factors [6].…”

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…The eCB system is also integral to regulation of emotional behavior, being essential to forms of synaptic plasticity that determine learning and response to emotionally salient, particularly highly aversive events [29,30]. Activation of CB 1 Rs produces anxiolytic effects in various models of unconditioned fear, relevant to multiple anxiety disorder symptom domains (reviewed in [30][31][32][33]).…”