Synaptogenic activity of the axon guidance molecule Robo2 underlies hippocampal circuit function

• Published in: Cell reports (Cambridge) 2021-10, Vol.37 (3), p.109828-109828, Article 109828
• Main Authors: Blockus, Heike, Rolotti, Sebi V., Szoboszlay, Miklos, Peze-Heidsieck, Eugénie, Ming, Tiffany, Schroeder, Anna, Apostolo, Nuno, Vennekens, Kristel M., Katsamba, Phinikoula S., Bahna, Fabiana, Mannepalli, Seetha, Ahlsen, Goran, Honig, Barry, Shapiro, Lawrence, de Wit, Joris, Losonczy, Attila, Polleux, Franck
• Format: Article
• Language: English
• Subjects: Animals; CA1 Region, Hippocampal - cytology; CA1 Region, Hippocampal - metabolism; CA3 Region, Hippocampal - cytology; CA3 Region, Hippocampal - metabolism; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; dendrites; Excitatory Postsynaptic Potentials; HEK293 Cells; hippocampus; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural Cell Adhesion Molecules - genetics; Neural Cell Adhesion Molecules - metabolism; neurexins; place cells; Place Cells - metabolism; Pyramidal Cells - metabolism; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Roundabout Proteins; Slit-Robo; synapse development; Synapses - metabolism; synaptic adhesion molecules; synaptic specificity
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109828

Synaptic connectivity within adult circuits exhibits a remarkable degree of cellular and subcellular specificity. We report that the axon guidance receptor Robo2 plays a role in establishing synaptic specificity in hippocampal CA1. In vivo, Robo2 is present and required postsynaptically in CA1 pyramidal neurons (PNs) for the formation of excitatory (E) but not inhibitory (I) synapses, specifically in proximal but not distal dendritic compartments. In vitro approaches show that the synaptogenic activity of Robo2 involves a trans-synaptic interaction with presynaptic Neurexins, as well as binding to its canonical extracellular ligand Slit. In vivo 2-photon Ca2+ imaging of CA1 PNs during spatial navigation in awake behaving mice shows that preventing Robo2-dependent excitatory synapse formation cell autonomously during development alters place cell properties of adult CA1 PNs. Our results identify a trans-synaptic complex linking the establishment of synaptic specificity to circuit function. [Display omitted] •The axon guidance receptors Robo1/2 can function as synaptogenic cues•Postsynaptic Robo forms a trans-synaptic complex with Slit and presynaptic Neurexin•Robo2 is required for formation of a subset of excitatory CA3 to CA1 synapses•Sparse deletion of Robo2 in CA1 pyramidal neurons impairs emergence of place cells Blockus et al. demonstrate that the axon guidance receptors Robo1/2 are synaptogenic cues required postsynaptically for the establishment of synaptic specificity between CA3 axons and dendrites of CA1 pyramidal neurons (PNs). Developmental deletion of Robo2 in CA1 PNs disrupts the emergence of place cell properties in adult hippocampus.