Endocannabinoid-dependent long-term depression in a nociceptive synapse requires coordinated presynaptic and postsynaptic transcription and translation.

Endocannabinoids (eCBs) play an important role in long-term regulation of synaptic signaling in both vertebrates and invertebrates. In this study, the role of transcription- and translation-dependent processes in presynaptic versus postsynaptic neurons was examined during eCB-mediated synaptic plasticity in the CNS of the leech. Low-frequency stimulation (LFS) of non-nociceptive afferents elicits eCB-dependent long-term depression (eCB-LTD) heterosynaptically in nociceptive synapses that lasts at least 2 h. Bath application of emetine, a protein synthesis inhibitor, blocked eCB-LTD after afferent LFS or exogenous eCB application, indicating that this depression was translation dependent. Bath application of actinomycin D, an irreversible RNA synthesis inhibitor, or 5,6-dichlorobenzimidazole 1-β-d-ribofurandoside (DRB), a reversible RNA synthesis inhibitor, also prevented eCB-LTD. Selective injection of DRB or emetine into the presynaptic or postsynaptic neuron before LFS indicated that eCB-LTD required transcription and translation in the postsynaptic neuron but only translation in the presynaptic cell. Depression observed immediately after LFS was also blocked when these transcription- and translation-dependent processes were inhibited. It is proposed that induction of eCB-LTD in this nociceptive synapse requires the coordination of presynaptic protein synthesis and postsynaptic mRNA and protein synthesis. These findings provide significant insights into both eCB-based synaptic plasticity and understanding how activity in non-nociceptive afferents modulates nociceptive pathways.