Transient information input to the brain leads to persistent changes in synaptic circuits, contributing to the formation of memory engrams. Pre- and postsynaptic structures undergo coordinated functional and structural changes during this process, but how such changes are achieved by their component molecules remains largely unknown. We found that activated CaMKII, a central player of synaptic plasticity, undergoes liquid–liquid phase separation with the NMDA-type glutamate receptor subunit GluN2B. Due to CaMKII autophosphorylation, the condensate stably persists even after Ca2+ is removed. The selective binding of activated CaMKII with GluN2B cosegregates AMPA receptors and the synaptic adhesion molecule neuroligin into a phase-in-phase assembly. In this way, Ca2+-induced liquid–liquid phase separation of CaMKII has the potential to act as an activity-dependent mechanism to crosslink postsynaptic proteins, which may serve as a platform for synaptic reorganization associated with synaptic plasticity.
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All relevant data of this manuscript are available from the corresponding author upon reasonable request. Protein sequences are available from NCBI (https://www.ncbi.nlm.nih.gov/protein/).
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We thank R. A. Nicoll, J. W. Hell and T. A. Blanpied for comments on the manuscript, E. Gouaux, O. Thoumine, M. Sainlos, M. Rosendale and Bordeaux Imaging Center for the reagents and assistance and L. Yu, A. Z. Weitemier and E. Agnello for editing. This work was supported by RIKEN Presidents Fund, SPIRITS 2019 of Kyoto University, Grant-in-Aid for Scientific Research JP20240032, JP22110006, JP16H01292, JP18H04733 and JP18H05434 from the MEXT, Japan, JST, CREST JPMJCR20E4, Japan, Programme Exploration France from Ambassade de France au Japon, The Uehara Memorial Foundation, The Naito Foundation, Research Foundation for Opto-Science and Technology, Novartis Foundation, The Takeda Science Foundation and Japan Foundation for Applied Enzymology to Y.H., The Takeda Science Foundation and Grants-in-Aid for Scientific Research JP17K14947, JP18KK0421 and JP19K06885 from the MEXT, Japan to T.H., grants from the Simons Foundation (Award ID 510178) and Research Grant Council of Hong Kong (AoE-M09-12 and C6004-17G) to M.Z., HFSP Research Grant (RGP0020/2019) jointly to Y.H. and M.Z, CRCNS-NIH-ANR AMPAR-T fellowship to E.H. and The National Center for Scientific Research (CNRS), Agence Nationale de la Recherche (DynHippo) to L.G. and J.F.
Y.H. is partly supported by Fujitsu Laboratories and Dwango.
Peer review information Nature Neuroscience thanks Thomas Biederer, Dragomir Milovanovic and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Hosokawa, T., Liu, PW., Cai, Q. et al. CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation. Nat Neurosci (2021). https://doi.org/10.1038/s41593-021-00843-3
Regulation of synaptic nanodomain by liquidâliquid phase separation: A novel mechanism of synaptic plasticity
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