PT - JOURNAL ARTICLE AU - Heike Blockus AU - Sebastian V. Rolotti AU - Miklos Szoboszlay AU - Tiffany Ming AU - Anna Schroeder AU - Kristel M. Vennekens AU - Phinikoula Katsamba AU - Fabiana Bahna AU - Seetha Mannepalli AU - Goran Ahlsen AU - Barry Honig AU - Lawrence Shapiro AU - Joris de Wit AU - Attila Losonczy AU - Franck Polleux TI - Synaptogenic activity of the axon guidance molecule Robo2 is critical for hippocampal circuit function AID - 10.1101/840710 DP - 2019 Jan 01 TA - bioRxiv PG - 840710 4099 - http://biorxiv.org/content/early/2019/11/13/840710.short 4100 - http://biorxiv.org/content/early/2019/11/13/840710.full AB - The developmental transition between axon guidance and synapse formation is critical for circuit assembly but still poorly understood at the molecular level. We hypothesized that this key transition could be regulated by axon guidance cues switching their function to regulate synaptogenesis with subcellular specificity. Here, we report evidence for such a functional switch, describing a novel role for the axon guidance molecule Robo2 in excitatory synapse formation onto dendrites of CA1 pyramidal neurons (PNs) in the mouse hippocampus. Cell-autonomous deletion of Robo2 from CA1 PNs leads to a drastic reduction of the number of excitatory synapses specifically in proximal dendritic compartments. At the molecular level, we show that this novel postsynaptic function of Robo2 depends on both its canonical ligand Slit and a novel interaction with presynaptic Neurexins. Biophysical analysis reveals that Robo2 binds directly to Neurexins via its Ig4-5 domains. In vivo 2-photon Ca2+ imaging of CA1 PNs during spatial navigation in mice shows that sparse deletion of Robo2 during development drastically reduces the likelihood of place cell emergence and alters spatial coding properties of the remaining place cells. Our results identify Robo2 as a novel molecular effector linking synaptic specificity to the acquisition of spatial coding properties characterizing hippocampal circuits.