The proteomic landscape of synaptic diversity across brain regions and cell types

Marc van Oostrum; Thomas M. Blok; Stefano L. Giandomenico; Susanne tom Dieck; Georgi Tushev; Nicole Fürst; Julian D. Langer; Erin M. Schuman

doi:10.1016/j.cell.2023.09.028

The proteomic landscape of synaptic diversity across brain regions and cell types

Marc van Oostrum
, Thomas M. Blok
, Stefano L. Giandomenico
, Susanne tom Dieck
, Georgi Tushev
, Nicole Fürst
, Julian D. Langer
, Erin M. Schuman

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Summary
Neurons build synaptic contacts using different protein combinations that define the specificity, function, and plasticity potential of synapses; however, the diversity of synaptic proteomes remains largely unexplored. We prepared synaptosomes from 7 different transgenic mouse lines with fluorescently labeled presynaptic terminals. Combining microdissection of 5 different brain regions with fluorescent-activated synaptosome sorting (FASS), we isolated and analyzed the proteomes of 18 different synapse types. We discovered ∼1,800 unique synapse-type-enriched proteins and allocated thousands of proteins to different types of synapses (https://syndive.org/
). We identify shared synaptic protein modules and highlight the proteomic hotspots for synapse specialization. We reveal unique and common features of the striatal dopaminergic proteome and discover the proteome signatures that relate to the functional properties of different interneuron classes. This study provides a molecular systems-biology analysis of synapses and a framework to integrate proteomic information for synapse subtypes of interest with cellular or circuit-level experiments.

Original language	English
Pages (from-to)	5411-5427.e23
Number of pages	40
Journal	Cell
Volume	186
Issue number	24
Early online date	1 Nov 2023
DOIs	https://doi.org/10.1016/j.cell.2023.09.028
Publication status	Published - 22 Nov 2023
Externally published	Yes

Funding

We thank the MPIBR Imaging Facility and the MPIBR Proteomics Facility for assistance with data acquisition. We thank the MPIBR Animal Facility and Guido Schmalbach and Fabian Bayer from the MPIBR workshop. We are grateful to the members of the Schuman lab. We thank Ina Bartnik, Teresa Spano, Christina Thum, and Belquis Nassim Assir for technical support; Etienne Herzog lab for sharing resources; and Julia Kuhl for graphical support. Funding: the Swiss National Science Foundation (SNSF) (P2EZP3_191820 and P400PB_199288), the Novartis Foundation for medical-biological research (22B079), and the Max Planck Society and the European Union (ERC, DiverseSynapse, 101054512). M.v.O. co-wrote the manuscript and performed all experiments except those noted below. T.M.B. performed immunoblotting, histology, and EM. S.L.G. performed proteasome experiments and immunoblotting. S.t.D. performed subfield dissections and contributed to methodology. G.T. contributed data analysis and developed https://syndive.org/. N.F. prepared synaptosomes. J.D.L. supervised proteomics. E.M.S. supervised the project and co-wrote the manuscript. The authors declare no competing interests. We thank the MPIBR Imaging Facility and the MPIBR Proteomics Facility for assistance with data acquisition. We thank the MPIBR Animal Facility and Guido Schmalbach and Fabian Bayer from the MPIBR workshop. We are grateful to the members of the Schuman lab. We thank Ina Bartnik, Teresa Spano, Christina Thum, and Belquis Nassim Assir for technical support; Etienne Herzog lab for sharing resources; and Julia Kuhl for graphical support. Funding: the Swiss National Science Foundation (SNSF) ( P2EZP3_191820 and P400PB_199288 ), the Novartis Foundation for medical-biological research ( 22B079 ), and the Max Planck Society and the European Union (ERC, DiverseSynapse, 101054512 ).

Funders	Funder number
MPIBR Imaging Facility
European Commission
European Research Council	101054512
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	P2EZP3_191820, P400PB_199288
Max-Planck-Gesellschaft
Novartis Stiftung für Medizinisch-Biologische Forschung	22B079

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title = "The proteomic landscape of synaptic diversity across brain regions and cell types",

abstract = "Summary Neurons build synaptic contacts using different protein combinations that define the specificity, function, and plasticity potential of synapses; however, the diversity of synaptic proteomes remains largely unexplored. We prepared synaptosomes from 7 different transgenic mouse lines with fluorescently labeled presynaptic terminals. Combining microdissection of 5 different brain regions with fluorescent-activated synaptosome sorting (FASS), we isolated and analyzed the proteomes of 18 different synapse types. We discovered ∼1,800 unique synapse-type-enriched proteins and allocated thousands of proteins to different types of synapses (https://syndive.org/ ). We identify shared synaptic protein modules and highlight the proteomic hotspots for synapse specialization. We reveal unique and common features of the striatal dopaminergic proteome and discover the proteome signatures that relate to the functional properties of different interneuron classes. This study provides a molecular systems-biology analysis of synapses and a framework to integrate proteomic information for synapse subtypes of interest with cellular or circuit-level experiments.",

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year = "2023",

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doi = "10.1016/j.cell.2023.09.028",

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AU - Oostrum, Marc van

AU - Blok, Thomas M.

AU - Giandomenico, Stefano L.

AU - Dieck, Susanne tom

AU - Tushev, Georgi

AU - Fürst, Nicole

AU - Langer, Julian D.

AU - Schuman, Erin M.

PY - 2023/11/22

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N2 - Summary Neurons build synaptic contacts using different protein combinations that define the specificity, function, and plasticity potential of synapses; however, the diversity of synaptic proteomes remains largely unexplored. We prepared synaptosomes from 7 different transgenic mouse lines with fluorescently labeled presynaptic terminals. Combining microdissection of 5 different brain regions with fluorescent-activated synaptosome sorting (FASS), we isolated and analyzed the proteomes of 18 different synapse types. We discovered ∼1,800 unique synapse-type-enriched proteins and allocated thousands of proteins to different types of synapses (https://syndive.org/ ). We identify shared synaptic protein modules and highlight the proteomic hotspots for synapse specialization. We reveal unique and common features of the striatal dopaminergic proteome and discover the proteome signatures that relate to the functional properties of different interneuron classes. This study provides a molecular systems-biology analysis of synapses and a framework to integrate proteomic information for synapse subtypes of interest with cellular or circuit-level experiments.

AB - Summary Neurons build synaptic contacts using different protein combinations that define the specificity, function, and plasticity potential of synapses; however, the diversity of synaptic proteomes remains largely unexplored. We prepared synaptosomes from 7 different transgenic mouse lines with fluorescently labeled presynaptic terminals. Combining microdissection of 5 different brain regions with fluorescent-activated synaptosome sorting (FASS), we isolated and analyzed the proteomes of 18 different synapse types. We discovered ∼1,800 unique synapse-type-enriched proteins and allocated thousands of proteins to different types of synapses (https://syndive.org/ ). We identify shared synaptic protein modules and highlight the proteomic hotspots for synapse specialization. We reveal unique and common features of the striatal dopaminergic proteome and discover the proteome signatures that relate to the functional properties of different interneuron classes. This study provides a molecular systems-biology analysis of synapses and a framework to integrate proteomic information for synapse subtypes of interest with cellular or circuit-level experiments.

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The proteomic landscape of synaptic diversity across brain regions and cell types

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