The kinase activity of EphA4 mediates homeostatic scaling-down of synaptic strength via activation of Cdk5

► EphA4 mediates activity-induced homeostatic down-regulation of mEPSCs. ► The kinase activity of EphA4 is necessary and sufficient for mEPSC scaling-down. ► The kinase activity of Cdk5, a downstream effector of EphA4, is also required. ► The activities of EphA4 and Cdk5 significantly increased during activity elevation. ► EphA4 protein level is eventually down-regulated, together with GluR1 and GluR2.