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

Nuno Apóstolo, Samuel N. Smukowski, Jeroen Vanderlinden, Giuseppe Condomitti, Vasily Rybakin, Jolijn ten Bos, Laura Trobiani, Sybren Portegies, Kristel M. Vennekens, Natalia V. Gounko, Davide Comoletti, Keimpe D. Wierda, Jeffrey N. Savas () and Joris de Wit ()
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Nuno Apóstolo: VIB Center for Brain & Disease Research
Samuel N. Smukowski: Northwestern University Feinberg School of Medicine
Jeroen Vanderlinden: VIB Center for Brain & Disease Research
Giuseppe Condomitti: VIB Center for Brain & Disease Research
Vasily Rybakin: Immunobiology, REGA Institute, Department of Microbiology and Immunology
Jolijn ten Bos: VIB Center for Brain & Disease Research
Laura Trobiani: Victoria University of Wellington
Sybren Portegies: VIB Center for Brain & Disease Research
Kristel M. Vennekens: VIB Center for Brain & Disease Research
Natalia V. Gounko: VIB Center for Brain & Disease Research
Davide Comoletti: Victoria University of Wellington
Keimpe D. Wierda: VIB Center for Brain & Disease Research
Jeffrey N. Savas: Northwestern University Feinberg School of Medicine
Joris de Wit: VIB Center for Brain & Disease Research

Nature Communications, 2020, vol. 11, issue 1, 1-21

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18956-x

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