Figure 3. Non-retrograde eCB signaling.

A, Mechanism underlying postsynaptic TRPV1-LTD. Presynaptic activity releases glutamate that stimulates mGluR5. Postsynaptic depolarization may also be required. mGluR5 couples to anandamide (AEA) production which activates TRPV1, leading to enhanced Ca²⁺ signaling. Ca²⁺ engages calcineurin/dynamin (CaN/Dyn), causing AMPA receptor (AMPAR) endocytosis and LTD. IC, intracellular compartment. N. Accumbens, nucleus accumbens; BNST, bed nucleus of the stria terminalis. B, Mechanism responsible for slow-self inhibition (autocrine signaling). Postsynaptic activity-induced Ca²⁺ elevation facilitates 2-AG production. 2-AG activates postsynaptic CB₁Rs that signal to a G protein-coupled inwardly rectifying K+ (GIRK) channel to hyperpolarize the membrane potential and inhibit neuronal firing. Dashed lines indicate putative pathways.