SorCS1-mediated sorting in dendrites maintains neurexin axonal surface polarization required for synaptic function

The pre- and postsynaptic membranes comprising the synaptic junction differ in protein composition. The mechanisms that maintain the polarized distribution of synaptic membrane proteins are poorly understood. The sorting receptor SorCS1 is a critical trafficking regulator of neuronal receptors, including neurexin (Nrxn), a presynaptic adhesion molecule essential for synaptic transmission. We find that SorCS1 controls a balance between axonal and dendritic Nrxn1 surface levels. Newly synthesized Nrxn1 traffics to the somatodendritic surface, followed by endocytosis. SorCS1 interacts with the Rab11 effector protein Rab11FIP5/Rip11 to facilitate the transition of internalized Nrxn1 from early to recycling endosomes and bias Nrxn1 surface polarization toward the axon. In the absence of SorCS1, Nrxn1 accumulates in early endosomes and mis-polarizes to the dendritic surface, impairing presynaptic function. The axonal/dendritic balance of Nrxn1 surface distribution is activity-dependent, indicating that SorCS1-mediated sorting in somatodendritic endosomes dynamically controls Nrxn1 axonal surface polarization required for proper presynaptic function.