Significance Synapses are controlled by transsynaptic adhesion complexes that mediate bidirectional signaling between pre- and postsynaptic compartments. Long-term potentiation (LTP) of synaptic transmission is thought to enable synaptic modifications during memory formation, but the signaling mechanisms involved remain poorly understood. We show that binding of cerebellin-4 (Cbln4), a secreted ligand of presynaptic neurexin adhesion molecules, to neogenin-1, a postsynaptic surface protein known as a developmental netrin receptor, is essential for normal LTP at entorhinal cortex→dentate gyrus synapses in mice. Cbln4 and neogenin-1 are dispensable for basal synaptic transmission and not involved in establishing synaptic connections as such. Our data identify a netrin receptor as a postsynaptic organizer of synaptic plasticity that collaborates specifically with the presynaptic neurexin–ligand Cbln4.