The developmental transition between axon guidance and synapse formation is critical for circuit assembly but still poorly understood. We present evidence that this key transition can be regulated by axon guidance cues switching their function to regulate synaptogenesis with subcellular specificity. We uncovered a novel role for the axon guidance molecule Robo2 in excitatory synapse formation in the mouse hippocampus. Cell-autonomous deletion of Robo2 from CA1 pyramidal neurons (PNs) leads to a drastic reduction of the number of excitatory synapses specifically in proximal dendritic compartments. We show that this postsynaptic function of Robo2 depends on both its canonical ligand Slit and a novel interaction with presynaptic Neurexins. 2-photon Ca2+ imaging of CA1 PNs during spatial navigation in mice shows that sparse deletion of Robo2 during development drastically alters the spatial coding properties of CA1 PNs. Our results identify Robo2 as a novel effector linking synaptic specificity to circuit function.
Dr. Heike Blockus
K99-NINDS fellow at Columbia University