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.

为了响应刺激，立即早期基因产物 Arc 可以通过从突触中去除 AMPA 受体（AMPAR）来急剧下调突触强度，从而调节突触可塑性。Arc（一种支架蛋白）如何特异性促进 AMPAR 的突触去除尚不清楚。我们发现 Arc 直接拮抗 PSD-95 与 TARP 的结合，TARP 是 AMPAR 的辅助亚基。Arc 以高度浓度敏感的方式，从通过相分离形成的突触后密度 (PSD) 凝聚物中急剧分散 TARP。尾部“PSY”基序中 Ser 残基磷酸化的 TARP 完全无法被 Arc 分散，这表明 Arc 无法在活动突触中从 PSD 中取代 AMPAR。相反，加强 Arc 和 TARP 之间的相互作用会增强 Arc 削弱突触的能力。因此，Arc可以通过调节PSD相分离来特异性且有效地调节突触AMPAR聚类。我们的研究进一步表明，PSD 凝聚体形成/分散的活动依赖性、双向调节代表了突触可塑性的一般调节机制。