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Synaptogenic activity of the axon guidance molecule Robo2 is critical for hippocampal circuit function

Heike Blockus, Sebastian V. Rolotti, Miklos Szoboszlay, Tiffany Ming, Anna Schroeder, Kristel M. Vennekens, Phinikoula Katsamba, Fabiana Bahna, Seetha Mannepalli, Goran Ahlsen, Barry Honig, Lawrence Shapiro, Joris de Wit, Attila Losonczy, View ORCID ProfileFranck Polleux
doi: https://doi.org/10.1101/840710
Heike Blockus
Department of Neuroscience, Columbia University, New York, NY 10027, USAZuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
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Sebastian V. Rolotti
Department of Neuroscience, Columbia University, New York, NY 10027, USAZuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
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Miklos Szoboszlay
Department of Neuroscience, Columbia University, New York, NY 10027, USAZuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
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Tiffany Ming
Department of Neuroscience, Columbia University, New York, NY 10027, USAZuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
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Anna Schroeder
VIB Center for Brain and Disease Research, Herestraat 49, 3000 Leuven, BelgiumDepartment of Neurosciences, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
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Kristel M. Vennekens
VIB Center for Brain and Disease Research, Herestraat 49, 3000 Leuven, BelgiumDepartment of Neurosciences, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
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Phinikoula Katsamba
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USADepartment of Biochemistry and Biophysics, Columbia University, New York, NY 10027, USA
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Fabiana Bahna
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USADepartment of Biochemistry and Biophysics, Columbia University, New York, NY 10027, USA
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Seetha Mannepalli
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USADepartment of Biochemistry and Biophysics, Columbia University, New York, NY 10027, USA
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Goran Ahlsen
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USADepartment of Biochemistry and Biophysics, Columbia University, New York, NY 10027, USA
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Barry Honig
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USADepartment of Biochemistry and Biophysics, Columbia University, New York, NY 10027, USA
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Lawrence Shapiro
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USADepartment of Biochemistry and Biophysics, Columbia University, New York, NY 10027, USA
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Joris de Wit
VIB Center for Brain and Disease Research, Herestraat 49, 3000 Leuven, BelgiumDepartment of Neurosciences, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
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Attila Losonczy
Department of Neuroscience, Columbia University, New York, NY 10027, USAZuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USAKavli Institute for Brain Science, Columbia University, New York, NY 10027, USA
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Franck Polleux
Department of Neuroscience, Columbia University, New York, NY 10027, USAZuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USAKavli Institute for Brain Science, Columbia University, New York, NY 10027, USA
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  • ORCID record for Franck Polleux
  • For correspondence: fp2304@columbia.edu
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Abstract

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.

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Posted November 13, 2019.
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Synaptogenic activity of the axon guidance molecule Robo2 is critical for hippocampal circuit function
Heike Blockus, Sebastian V. Rolotti, Miklos Szoboszlay, Tiffany Ming, Anna Schroeder, Kristel M. Vennekens, Phinikoula Katsamba, Fabiana Bahna, Seetha Mannepalli, Goran Ahlsen, Barry Honig, Lawrence Shapiro, Joris de Wit, Attila Losonczy, Franck Polleux
bioRxiv 840710; doi: https://doi.org/10.1101/840710
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Synaptogenic activity of the axon guidance molecule Robo2 is critical for hippocampal circuit function
Heike Blockus, Sebastian V. Rolotti, Miklos Szoboszlay, Tiffany Ming, Anna Schroeder, Kristel M. Vennekens, Phinikoula Katsamba, Fabiana Bahna, Seetha Mannepalli, Goran Ahlsen, Barry Honig, Lawrence Shapiro, Joris de Wit, Attila Losonczy, Franck Polleux
bioRxiv 840710; doi: https://doi.org/10.1101/840710

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