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 memory is well established, but the molecular mechanisms that enable this circuit to mediate pattern separation memory are incompletely understood. We previously found that a trans-synaptic protein complex formed by presynaptic Cerebellin-4 and postsynaptic Neogenin-1 is selectively required for long-term potentiation (LTP) in the EC→DG circuit. We now demonstrate that this complex is essential for normal pattern separation memory, suggesting a role for this form of LTP in pattern separation memory. Deletion of either presynaptic Cerebellin-4 in the entorhinal cortex or of postsynaptic Neogenin-1 in the dentate gyrus impaired pattern separation but did not affect pattern completion 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.