CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation

Tomohisa Hosokawa, Pin-Wu Liu, Qixu Cai, Joana S. Ferreira, Florian Levet, Corey Butler, Jean-Baptiste Sibarita, Daniel Choquet, Laurent Groc, Eric Hosy, Mingjie Zhang, Yasunori Hayashi
Nat Neurosci. 2021-04-29; :
DOI: 10.1038/s41593-021-00843-3

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Hosokawa T(#)(1)(2)(3), Liu PW(#)(1), Cai Q(4), Ferreira JS(5), Levet F(5), Butler C(5), Sibarita JB(5), Choquet D(5)(6), Groc L(5), Hosy E(5), Zhang
M(7)(8), Hayashi Y(9).

Author information:
(1)Department of Pharmacology, Kyoto University Graduate School of Medicine,  Kyoto, Japan.
(2)RIKEN Brain Science Institute, Saitama, Japan.
(3)Department of Molecular Biology, Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan.
(4)Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.
(5)Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France.
(6)Bordeaux Imaging Center, Bordeaux, France.
(7)Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China. .
(8)School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. .
(9)Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan. .
(#)Contributed equally

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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