B-ephrin reverse signaling is required for NMDA-independent long-term potentiation of mossy fibers in the hippocampus.

The mossy fiber to CA3 pyramidal neuron synapse in the hippocampus displays an atypical form of NMDA receptor-independent long-term potentiation (LTP). Plasticity at this synapse is expressed in the presynaptic terminal as an elevated probability of neurotransmitter release. However, evidence indicates that postsynaptic mechanisms and trans-synaptic signaling through an association between postsynaptic EphB receptors and presynaptic B-ephrins are necessary for the induction of LTP. Here we show that ephrin-B3 protein is highly expressed in mossy fiber axons and terminals. There are specific deficits in mossy fiber LTP in mice in which the cytoplasmic C-terminal signaling domain of the ephrin-B3 protein is replaced with beta-galactosidase. These deficits are not observed in ephrin-B3 null mutant mice because of functional redundancy by virtue of other B-ephrins. These results indicate that B-ephrin reverse signaling into the presynaptic mossy fiber bouton is required for the induction of NMDA receptor-independent LTP at this synapse.