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Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer

Author

Listed:
  • Nuno Apóstolo

    (VIB Center for Brain & Disease Research
    KU Leuven, Department of Neurosciences, Leuven Brain Institute)

  • Samuel N. Smukowski

    (Northwestern University Feinberg School of Medicine)

  • Jeroen Vanderlinden

    (VIB Center for Brain & Disease Research
    KU Leuven, Department of Neurosciences, Leuven Brain Institute)

  • Giuseppe Condomitti

    (VIB Center for Brain & Disease Research
    KU Leuven, Department of Neurosciences, Leuven Brain Institute)

  • Vasily Rybakin

    (Immunobiology, REGA Institute, Department of Microbiology and Immunology)

  • Jolijn ten Bos

    (VIB Center for Brain & Disease Research
    KU Leuven, Department of Neurosciences, Leuven Brain Institute)

  • Laura Trobiani

    (Victoria University of Wellington)

  • Sybren Portegies

    (VIB Center for Brain & Disease Research
    KU Leuven, Department of Neurosciences, Leuven Brain Institute)

  • Kristel M. Vennekens

    (VIB Center for Brain & Disease Research
    KU Leuven, Department of Neurosciences, Leuven Brain Institute)

  • Natalia V. Gounko

    (VIB Center for Brain & Disease Research
    KU Leuven, Department of Neurosciences, Leuven Brain Institute
    Electron Microscopy Platform & VIB BioImaging Core)

  • Davide Comoletti

    (Victoria University of Wellington
    Child Health Institute of New Jersey, and Departments of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University)

  • Keimpe D. Wierda

    (VIB Center for Brain & Disease Research
    KU Leuven, Department of Neurosciences, Leuven Brain Institute)

  • Jeffrey N. Savas

    (Northwestern University Feinberg School of Medicine)

  • Joris de Wit

    (VIB Center for Brain & Disease Research
    KU Leuven, Department of Neurosciences, Leuven Brain Institute)

Abstract

Excitatory and inhibitory neurons are connected into microcircuits that generate circuit output. Central in the hippocampal CA3 microcircuit is the mossy fiber (MF) synapse, which provides powerful direct excitatory input and indirect feedforward inhibition to CA3 pyramidal neurons. Here, we dissect its cell-surface protein (CSP) composition to discover novel regulators of MF synaptic connectivity. Proteomic profiling of isolated MF synaptosomes uncovers a rich CSP composition, including many CSPs without synaptic function and several that are uncharacterized. Cell-surface interactome screening identifies IgSF8 as a neuronal receptor enriched in the MF pathway. Presynaptic Igsf8 deletion impairs MF synaptic architecture and robustly decreases the density of bouton filopodia that provide feedforward inhibition. Consequently, IgSF8 loss impairs excitation/inhibition balance and increases excitability of CA3 pyramidal neurons. Our results provide insight into the CSP landscape and interactome of a specific excitatory synapse and reveal IgSF8 as a critical regulator of CA3 microcircuit connectivity and function.

Suggested Citation

  • Nuno Apóstolo & Samuel N. Smukowski & Jeroen Vanderlinden & Giuseppe Condomitti & Vasily Rybakin & Jolijn ten Bos & Laura Trobiani & Sybren Portegies & Kristel M. Vennekens & Natalia V. Gounko & David, 2020. "Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer," Nature Communications, Nature, vol. 11(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18956-x
    DOI: 10.1038/s41467-020-18956-x
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