Pattern separation memory requires Cerebellin 4-Neogenin 1 signaling at dentate gyrus synapses

The ability to avoid confusion between similar episodic memories enables organismal survival and fitness. This evolutionarily conserved differentiation process of memories as distinct representations is known as pattern separation. A central role for the entorhinal cortex->dentate gyrus (EC->DG) circuit in pattern separation is well established, but the molecular mechanisms that enable this circuit to mediate pattern separation memory is not known. Here we show the involvement in murine pattern separation memory of a unique transsynaptic protein complex formed by Cerebellin-4, Neogenin-1, and neurexins that is known to be selectively required for long-term plasticity in the EC->DG circuit. In vivo deletion of either presynaptic Cerebellin-4 in the entorhinal cortex or of postsynaptic Neogenin-1 in the dentate gyrus impairs acquisition of pattern separation memory. Thus, we describe a specific memory function for a defined molecular complex at an identified synapse, providing direct support for the hypothesis that synaptic plasticity contributes to the encoding of memory.