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

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posted on 04.08.2022, 22:18 authored by N Apóstolo, SN Smukowski, J Vanderlinden, G Condomitti, V Rybakin, J ten Bos, L Trobiani, S Portegies, KM Vennekens, NV Gounko, Davide ComolettiDavide Comoletti, KD Wierda, JN Savas, J de Wit
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.

Funding

Collaborative Research: Structure and Function of Reelin in Brain Development | Funder: RUTGERS UNIVERSITY | Grant ID: 1755189

History

Preferred citation

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), 5171-. https://doi.org/10.1038/s41467-020-18956-x

Journal title

Nature Communications

Volume

11

Issue

1

Publication date

01/12/2020

Pagination

5171

Publisher

Springer Science and Business Media LLC

Publication status

Published

Online publication date

14/10/2020

ISSN

2041-1723

eISSN

2041-1723

Article number

5171

Language

en