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Significance The delta glutamate receptors (GluD1 and GluD2) shared high homology with ionotropic glutamate receptors but, surprisingly, are not gated by glutamate, or any other known ligand. GluD2 is only expressed in cerebellar Purkinje cells, where it forms a scaffolding complex with Cbln1 and presynaptic neurexin 1β (+S4). Might other synapses in the brain use a similar mechanism? We have found that GluD1, a long-neglected receptor subtype, powerfully and specifically regulates synapses in the hippocampus. We show that Cbln2 interacts with GluD1 and presynaptic neurexin 1β (+S4). This tripartite complex plays critical roles in both synaptogenesis and maintenance. Finally, we provide evidence that our results likely apply to synapses throughout the forebrain where GluD1 is widely expressed.

Postsynaptic δ1 glutamate receptor assembles and maintains hippocampal synapses via Cbln2 and neurexin