Molecular mechanism of hippocampal long-term potentiation – Towards multiscale understanding of learning and memory

•The expression mechanism of long-term potentiation is now explained in molecular term by AMPA-R trafficking.•However the mechanism to maintain the enhanced transmission despite protein diffusion and turnover still remains elusive.•A recent emergence of liquid-liquid phase separation of synaptic molecules including CaMKII might explain this. Long-term potentiation (LTP) of synaptic transmission is considered to be a cellular counterpart of learning and memory. Activation of postsynaptic NMDA type glutamate receptor (NMDA-R) induces trafficking of AMPA type glutamate receptors (AMPA-R) and other proteins to the synapse in sequential fashion. At the same time, the dendritic spine expands for long-term and modulation of actin underlies this (structural LTP or sLTP). How these changes persist despite constant diffusion and turnover of the component proteins have been the central focus of the current LTP research. Signaling triggered by Ca2+-influx via NMDA-R triggers kinase including Ca2+/calmodulin-dependent protein kinase II (CaMKII). CaMKII can sustain longer-term biochemical signaling by forming a reciprocally-activating kinase-effector complex with its substrate proteins including Tiam1, thereby regulating persistence of the downstream signaling. Furthermore, activated CaMKII can condense at the synapse through the mechanism of liquid-liquid phase separation (LLPS). This increases the binding capacity at the synapse, thereby contributing to the maintenance of enlarged protein complexes. It may also serve as the synapse tag, which captures newly synthesized proteins.