The ubiquitin-proteasome system and learning-dependent synaptic plasticity - A 10 year update

Over 25 years ago, a seminal paper demonstrated that the ubiquitin-proteasome system (UPS) was involved in activity-dependent synaptic plasticity. Interest in this topic began to expand around 2008 following another seminal paper showing that UPS-mediated protein degradation controlled the "destabilization" of memories following retrieval, though we remained with only a basic understanding of how the UPS regulated activity- and learning-dependent synaptic plasticity. However, over the last 10 years there has been an explosion of papers on this topic that has significantly changed our understanding of how ubiquitin-proteasome signaling regulates synaptic plasticity and memory formation. Importantly, we now know that the UPS controls much more than protein degradation, is involved in plasticity underlying drugs of abuse and that there are significant sex differences in how ubiquitin-proteasome signaling is used for memory storage processes. Here, we aim to provide a critical 10-year update on the role of ubiquitin-proteasome signaling in synaptic plasticity and memory formation, including updated cellular models of how ubiquitin-proteasome activity could be regulating learning-dependent synaptic plasticity in the brain.