Ca 2+ /calmodulin binding to PSD ‐95 mediates homeostatic synaptic scaling down

Postsynaptic density protein‐95 ( PSD ‐95) localizes AMPA ‐type glutamate receptors ( AMPAR s) to postsynaptic sites of glutamatergic synapses. Its postsynaptic displacement is necessary for loss of AMPAR s during homeostatic scaling down of synapses. Here, we demonstrate that upon Ca 2+ influx, Ca 2+ /calmodulin (Ca 2+ /CaM) binding to the N‐terminus of PSD ‐95 mediates postsynaptic loss of PSD ‐95 and AMPAR s during homeostatic scaling down. Our NMR structural analysis identified E17 within the PSD‐95 N‐terminus as important for binding to Ca 2+ /CaM by interacting with R126 on CaM. Mutating E17 to R prevented homeostatic scaling down in primary hippocampal neurons, which is rescued via charge inversion by ectopic expression of Ca M R 126E , as determined by analysis of miniature excitatory postsynaptic currents. Accordingly, increased binding of Ca 2+ /CaM to PSD ‐95 induced by a chronic increase in Ca 2+ influx is a critical molecular event in homeostatic downscaling of glutamatergic synaptic transmission.