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; Joris de Wit

doi:10.1038/s41467-020-18956-x

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^*, Joris de Wit^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

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.

Original language	English (US)
Article number	5171
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18956-x
State	Published - Dec 1 2020

Funding

We thank Franck Polleux, Dietmar Schmucker, Pierre Vanderhaeghen, Anirvan Ghosh, Dan Dascenco, Lu\u00EDs Ribeiro, and Sara Calafate for critical reading of the manuscript, and De Wit lab members for helpful discussion and comments. We thank Pier Andr\u00E9e Penttila and Christ\u00E8le Nkama (VIB-KU Leuven FACS Core), the VIB-KU Leuven BioImaging Core, Joris Vandenbempt, and Brenda Luong for experimental help; Nicola Fattorelli for data visualization advice; Etienne Herzog and Matthew Holt for experimental advice. Leica SP8x confocal microscope was provided by InfraMouse (KU Leuven-VIB) through a Hercules type 3 project (ZW09-03). N.A. is supported by the Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia (FCT, Grant Number SFRH/BD/128869/2017). D.C. is supported by NSF IOS Grant #1755189, RWJ Foundation Grant #74260, and Research for Life (WMRF) 2019/301. J.N.S. is supported by R01AG061787. J.d.W is supported by ERC Starting Grant (#311083), FWO Odysseus Grant, FWO Project Grant G0C4518N, FWO EOS Grant G0H2818N, and Methusalem Grant of KU Leuven/Flemish Government.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Apóstolo, N., Smukowski, S. N., Vanderlinden, J., Condomitti, G., Rybakin, V., ten Bos, J., Trobiani, L., Portegies, S., Vennekens, K. M., Gounko, N. V., Comoletti, D., Wierda, K. D., Savas, J. N., & de Wit, J. (2020). Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer. Nature communications, 11(1), Article 5171. https://doi.org/10.1038/s41467-020-18956-x

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title = "Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer",

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.",

author = "Nuno Ap{\'o}stolo and Smukowski, {Samuel N.} and Jeroen Vanderlinden and Giuseppe Condomitti and Vasily Rybakin and {ten Bos}, Jolijn and Laura Trobiani and Sybren Portegies and Vennekens, {Kristel M.} and Gounko, {Natalia V.} and Davide Comoletti and Wierda, {Keimpe D.} and Savas, {Jeffrey N.} and {de Wit}, Joris",

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Apóstolo, N, Smukowski, SN, Vanderlinden, J, Condomitti, G, Rybakin, V, ten Bos, J, Trobiani, L, Portegies, S, Vennekens, KM, Gounko, NV, Comoletti, D, Wierda, KD, Savas, JN & de Wit, J 2020, 'Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer', Nature communications, vol. 11, no. 1, 5171. https://doi.org/10.1038/s41467-020-18956-x

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T1 - Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer

AU - Apóstolo, Nuno

AU - Smukowski, Samuel N.

AU - Vanderlinden, Jeroen

AU - Condomitti, Giuseppe

AU - Rybakin, Vasily

AU - ten Bos, Jolijn

AU - Trobiani, Laura

AU - Portegies, Sybren

AU - Vennekens, Kristel M.

AU - Gounko, Natalia V.

AU - Comoletti, Davide

AU - Wierda, Keimpe D.

AU - Savas, Jeffrey N.

AU - de Wit, Joris

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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

Abstract

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