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

Abstract

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.

Presynaptic FMRP and local protein synthesis support structural and functional plasticity of glutamatergic axon terminals

“…These findings are significant in that protein synthesis is a key mechanism of dendritic spine remodeling associated with postsynaptic forms of plasticity (Nakahata and Yasuda, 2018;Sutton and Schuman, 2006), but its presynaptic function has been heretofore unclear. Along with local protein degradation (Cohen and Ziv, 2017;Monday et al, 2020), local regulation of energy production (Rangaraju et al, 2014), and local structural change, the general acceptance that local protein synthesis occurs in presynaptic compartments supports the notion that presynaptic compartments are discrete, computationally-independent units, akin to dendritic spines.…”

Action potential-coupled Rho GTPase signaling drives presynaptic plasticity

“…We propose this new form of structural plasticity will be informed by the highly diverse nature of actin regulatory proteins enriched in presynaptic terminals, like that of the postsynapse. In support of this idea, actin remodeling was recently shown to be involved in a form of long-term depression at GABAergic terminals that is mediated by retrograde cannabinoid signaling ( Monday et al, 2020 ).…”

The Absence of the Transient Receptor Potential Vanilloid 1 Directly Impacts on the Expression and Localization of the Endocannabinoid System in the Mouse Hippocampus

“…The endocannabinod system (ECS) made up of cannabinoid receptors (CB 1 R, CB 2 R, among others), the main endocannabinoids, 2-arachydonoyl-glycerol (2-AG) and anandamide (AEA), the main synthesizing enzymes for 2-AG (diacylglycerol lipase, DAGL) and AEA (N-acyl phosphatidylethanolamine phospholipase D, NAPE-PLD), and their main degrading enzymes (2-AG: monoacylglycerol lipase, MAGL; AEA: fatty acid amide hydrolase, FAAH) as well as transport proteins, plays an essential role in hippocampal synaptic plasticity (Kano et al, 2009 ; Castillo et al, 2012 ; Maccarrone, 2017 ; Monday et al, 2020 ). Although the main enzymes for synthesis and degradation of 2-AG and AEA are selectively segregated at either presynaptic or postsynaptic sites (Gulyas et al, 2004 ; Katona et al, 2006 ; Yoshida et al, 2006 ; Blankman et al, 2007 ; Lafourcade et al, 2007 ; Starowicz et al, 2007 ; Puente et al, 2011 ; Reguero et al, 2011 ; Suárez et al, 2011 ) redundant pathways for 2-AG and AEA turnover also exit (for review, see Murataeva et al, 2014 ).…”