Roles of phospholipase Cβ and NMDA receptor in activity-d epen dent endocannabinoid release

Endocannabinoids are released from postsynaptic neurons, activate presynaptic cannabinoid receptors and cause various forms of short-term and long-term synaptic plasticity throughout the brain. Using hippocampal and cerebellar neurons, we have revealed that endocannabinoid release can be induced through two different pathways. One is independent of phospholipase C,3 (PLC,3) and driven by Ca2+ elevation alone (Ca2+-driven endocannabinoid release, CaER), and the other is PLC beta-dependent and driven by activation of G(q/11)-coupled receptors (receptor-driven endocannabinoid release, RER). CaER is induced by activation of either voltage-gated Ca2+ channels or NMDA receptors. RER is functional even at resting Ca2+ levels (basal RER), but markedly enhanced by a small Ca2+ elevation (Ca2+-assisted RER). In Ca2+-assisted RER, PLC beta serves as a coincidence detector of receptor activation and Ca2+ elevation. We have also demonstrated that Ca2+-assisted RER is essential for the endocannabinoid release triggered by synaptic activity. Our anatomical data show that a set of receptors and enzymes required for RER are well organized so that the excitatory input can trigger RER effectively. Certain forms of spike-timing-dependent plasticity (STDP) are reported to depend on endocannabinoid signalling. The NMDA receptor and PLC,3 might play key roles in the endocannabinoid-dependent forms of STDP as coincidence detectors with different timing dependences.