Roles of phospholipase Cβ and NMDA receptor in activity-dependent endocannabinoid release

摘要

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 Cβ (PLCβ) and driven by Ca²⁺ elevation alone (Ca²⁺-driven endocannabinoid release, CaER), and the other is PLCβ-dependent and driven by activation of Gq/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, PLCβ 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 PLCβ might play key roles in the endocannabinoid-dependent forms of STDP as coincidence detectors with different timing dependences.