CB₁-receptor-mediated inhibitory LTD triggers presynaptic remodeling via protein synthesis and ubiquitination

Long-lasting forms of postsynaptic plasticity commonly involve protein synthesis-dependent structural changes of dendritic spines. However, the relationship between protein synthesis and presynaptic structural plasticity remains unclear. Here, we investigated structural changes in cannabinoid-receptor 1 (CB₁)-mediated long-term depression of inhibitory transmission (iLTD), a form of presynaptic plasticity that involves a protein-synthesis-dependent long-lasting reduction in GABA release. We found that CB₁-iLTD in acute rat hippocampal slices was associated with protein synthesis-dependent presynaptic structural changes. Using proteomics, we determined that CB₁ activation in hippocampal neurons resulted in increased ribosomal proteins and initiation factors, but decreased levels of proteins involved in regulation of the actin cytoskeleton, such as ARPC2 and WASF1/WAVE1, and presynaptic release. Moreover, while CB₁-iLTD increased ubiquitin/proteasome activity, ubiquitination but not proteasomal degradation was critical for structural and functional presynaptic CB₁-iLTD. Thus, CB₁-iLTD relies on both protein synthesis and ubiquitination to elicit structural changes that underlie long-term reduction of GABA release.