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

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. (C)& nbsp;2021 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.

Automated summary

Long-term potentiation (LTP) of synaptic transmission is considered as the cellular basis of learning and memory. Activation of NMDA-R triggers the movement of AMPA-R and other proteins, while dendritic spine expands with actin modulation. CaMKII sustains long-term signaling by forming a reciprocally-activating complex with its substrate proteins. Additionally, activated CaMKII can condense at the synapse through liquid-liquid phase separation, increasing binding capacity and capturing newly synthesized proteins.