Molecular Mechanisms Underlying Synaptic Tagging and Consolidation

After a synapse undergoes long-term potentiation (LTP), it acquires a newly remodeled molecular and structural organization. This reorganization over time is explained by a hypothetical structure called a synaptic tag, which is specifically formed at potentiated synapses, not at unstimulated ones, and captures newly synthesized proteins to persistently stabilize the potentiated state. However, to date, the molecular identity of the synaptic tag remains unclear. Based on several lines of experimental evidence, we propose that remodeled filamentous (F-) actin and CaMKII together form the synaptic tag by modifying the postsynaptic cytoskeletal structure to capture newly synthesized synaptic proteins. Liquid–liquid phase separation, a biophysical property of biological macromolecules, also plays a key role in this process. F-actin and CaMKII both fulfill the criteria to be the tag: they are specifically enriched at potentiated synapses without requiring new protein synthesis and persist for at least 1 h. Additionally, the intrinsic binding capacity of F-actin and CaMKII is ideal for capturing newly synthesized proteins at the synapse, thereby consolidating the synaptic structure and function and eventually allowing memory persistence.