RESUMO
Five decades ago, long-term potentiation (LTP) of synaptic transmission was discovered at entorhinal cortexâdentate gyrus (ECâDG) synapses, but the molecular determinants of ECâDG LTP remain largely unknown. Here, we show that the presynaptic neurexinligand cerebellin-4 (Cbln4) is highly expressed in the entorhinal cortex and essential for LTP at ECâDG synapses, but dispensable for basal synaptic transmission at these synapses. Cbln4, when bound to cell-surface neurexins, forms transcellular complexes by interacting with postsynaptic DCC (deleted in colorectal cancer) or neogenin-1. DCC and neogenin-1 act as netrin and repulsive guidance molecule-a (RGMa) receptors that mediate axon guidance in the developing brain, but their binding to Cbln4 raised the possibility that they might additionally function in the mature brain as postsynaptic receptors for presynaptic neurexin/Cbln4 complexes, and that as such receptors, DCC or neogenin-1 might mediate ECâDG LTP that depends on Cbln4. Indeed, we observed that neogenin-1, but not DCC, is abundantly expressed in dentate gyrus granule cells, and that postsynaptic neogenin-1 deletions in dentate granule cells blocked ECâDG LTP, but again did not affect basal synaptic transmission similar to the presynaptic Cbln4 deletions. Thus, binding of presynaptic Cbln4 to postsynaptic neogenin-1 renders ECâDG synapses competent for LTP, but is not required for establishing these synapses or for otherwise enabling their function.