The Rab5 guanylate exchange factor Rin1 regulates endocytosis of the EphA4 receptor in mature excitatory neurons.

Ephrin signaling through Eph receptor tyrosine kinases regulates important morphogenetic events during development and synaptic plasticity in the adult brain. Although Eph-ephrin endocytosis is required for repulsive axon guidance, its role in postnatal brain and synaptic plasticity is unknown. Here, we show that Rin1, a postnatal brain-specific Rab5-GEF, is coexpressed with EphA4 in excitatory neurons and interacts with EphA4 in synaptosomal fractions. The interaction of Rin1 and EphA4 requires Rin1's SH2 domain, consistent with the view that Rin1 targets tyrosine phosphorylated receptors to Rab5 compartments. We find that Rin1 mediates EphA4 endocytosis in postnatal amygdala neurons after engagement of EphA4 with its cognate ligand ephrinB3. Rin1 was shown to suppress synaptic plasticity in the amygdala, a forebrain structure important for fear learning, possibly by internalizing synaptic receptors. We find that the EphA4 receptor is required for synaptic plasticity in the amygdala, raising the possibility that an underlying mechanism of Rin1 function in amygdala is to down-regulate EphA4 signaling by promoting its endocytosis.