Figure 2. Potential mechanisms of associativity involved in eCB-LTD induction.

Postsynaptic compartment (left): the postsynaptic neuron can integrate action potential firing (which promotes Ca²⁺ rise via VDCCs) and synaptic release of glutamate (which activates mGluR-I) to facilitate eCB mobilization and eCB-LTD induction. Other Ca²⁺ sources (e.g. NMDARs and Ca²⁺ internal stores) could also contribute. In this model, PLC operates as a coincidence detector (61). Presynaptic compartment (right): the presynaptic terminal can also integrate two signals, eCBs (which activate presynaptic CB1Rs) and presynaptic firing (which promotes a Ca²⁺ rise via VDCCs and NMDARs). Ca²⁺ stores (endoplasmic reticulum, ER) may also contribute to this process. The presynaptic NMDAR may operate as a coincidence detector during a brief time window (26). In addition, the activity-dependent Ca²⁺ rise that occurs during minutes of CB1R activation likely promotes dephosphorylation of a presynaptic target downstream of the CB1R, the latter of which is an essential step for eCB-LTD induction (78).