Arc weakens synapses by dispersing AMPA receptors from postsynaptic density via modulating PSD phase separation

Chen, Xudong1; Jia, Bowen1; Araki, Yoichi2,3; Liu, Bian2,3; Ye, Fei1; Huganir, Richard2,3; Zhang, Mingjie1,4

2022-07-01

10.1038/s41422-022-00697-9

CELL RESEARCH   Impact Factor & Quartile

1001-0602

1748-7838

In response to stimuli, the immediate early gene product Arc can acutely down-regulate synaptic strength by removing AMPA receptors (AMPARs) from synapses and thus regulate synaptic plasticity. How Arc, a scaffold protein, can specifically facilitate synaptic removal of AMPARs is unknown. We found that Arc directly antagonizes with PSD-95 in binding to TARPs, which are the auxiliary subunits of AMPARs. Arc, in a highly concentration-sensitive manner, acutely disperses TARPs from the postsynaptic density (PSD) condensate formed via phase separation. TARPs with the Ser residue in the "P-S-Y"-motif of its tail phosphorylated are completely refractory from being dispersed by Arc, suggesting that Arc cannot displace AMPARs from PSDs in active synapses. Conversely, strengthening the interaction between Arc and TARPs enhances Arc's capacity in weakening synapses. Thus, Arc can specifically and effectively modulate synaptic AMPAR clustering via modulating PSD phase separation. Our study further suggests that activity-dependent, bi-directional modulation of PSD condensate formation/dispersion represents a general regulatory mechanism for synaptic plasticity.

SCI

English

Corresponding

Minister of Science and Technology of China[2019YFA0508402] ; National Science Foundation of China[82188101] ; Research Grant Council of Hong Kong["AoE-M09-12","16104518","16101419"] ; HFSP Research Grant[RGP0020/2019] ; National Institute of Health[RO1 NS036715]

Cell Biology

Cell Biology

WOS:000826806700002

SPRINGERNATURE

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Hong Kong Univ Sci & Technol, Div Life Sci, Kowloon, Clear Water Bay, Hong Kong, Peoples R China
2.Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
3.Johns Hopkins Univ, Sch Med, Kavli Neurosci Discovery Inst, Baltimore, MD 21205 USA
4.Southern Univ Sci & Technol, Sch Life Sci, Shenzhen, Guangdong, Peoples R China

Chen, Xudong,Jia, Bowen,Araki, Yoichi,et al. Arc weakens synapses by dispersing AMPA receptors from postsynaptic density via modulating PSD phase separation[J]. CELL RESEARCH,2022.

Chen, Xudong.,Jia, Bowen.,Araki, Yoichi.,Liu, Bian.,Ye, Fei.,...&Zhang, Mingjie.(2022).Arc weakens synapses by dispersing AMPA receptors from postsynaptic density via modulating PSD phase separation.CELL RESEARCH.

Chen, Xudong,et al."Arc weakens synapses by dispersing AMPA receptors from postsynaptic density via modulating PSD phase separation".CELL RESEARCH (2022).