Production and degradation of an endocannabinoid, 2-arachidonoylglycerol, during Ca²⁺-induced retrograde suppression of synaptic transmission

Abstract

Endocannabinoids (eCBs) are lipid mediators and serve as retrograde messengers at synapses in various brain regions. eCBs are produced and released on demand in activity-dependent manners, bind to presynaptic CB1 receptors, and cause short- or long-term suppression of transmitter release. Previous studies have revealed that eCB-mediated retrograde synaptic suppression is induced by Ca²⁺ influx into postsynaptic neurons through voltage-gated Ca²⁺ channels. We tested whether Ca²⁺ entry through NMDA receptors (NMDARs) can trigger eCB release. Using cultured hippocampal neurons, we demonstrated that NMDA transiently suppressed cannabinoid-sensitive IPSCs. This NMDA-induced suppression was eliminated by blocking NMDARs and CB1 receptors, and was significantly reduced by intracellular BAPTA. These results indicate that NMDAR activation caused Ca²⁺ influx into postsynaptic neurons and induced eCB release. We then examined how released eCBs are degraded and eCB signaling is consequently terminated. We found that inhibition of monoacylglycerol lipase (MGL), a hydrolyzing enzyme of the major eCB 2-arachidonoylglycerol, markedly prolonged the suppression of IPSCs induced by Ca²⁺ influx. Together with the anatomical evidence for the localization of MGL in presynaptic terminals, our data indicate that presynaptic MGL contributes to termination of retrograde eCB signaling. [J Physiol Sci. 2008;58 Suppl:S17]