Synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons
Open accessPublished version of a preprint
Abstract
Cortical layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons are embedded in distinct information processing pathways. Their morphology, connectivity, electrophysiological properties, and role in behavior have been extensively analyzed. However, the molecular composition of their synapses remains largely uncharacterized. Here, we dissect the protein composition of the excitatory postsynaptic compartment of mouse L5 neurons in intact somatosensory circuits, using an optimized proximity biotinylation workflow with high spatial accuracy. We find distinct synaptic signatures of L5 IT and PT neurons that are defined by proteins regulating synaptic organization and transmission, including cell-surface proteins (CSPs), neurotransmitter receptors and ion channels. In addition, we find a differential vulnerability to disease, with a marked enrichment of autism risk genes in the synaptic signature of L5 IT neurons compared to PT neurons. These results align with human studies and suggest that the excitatory postsynaptic compartment of L5 IT neurons is susceptible in autism. Our approach is versatile and can be broadly applied to other neuron types to create a protein-based, synaptic atlas of cortical circuits.
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Cites
Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · cited 1× · see citing works
“While it has been reported that mRNA and protein rarely match at absolute levels, it has also been shown that mRNA can predict proteomic differences at a global level 51–53 .”
Hafemeister, C., & Satija, R. (2019) · Genome Biology · doi:10.1186/s13059-019-1874-1 · Cited by 4,479 · see citing works
Mapping genomic loci implicates genes and synaptic biology in schizophrenia
Trubetskoy, V., Pardiñas, A. F., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T. B., Bryois, J., Chen, C.-Y., Dennison, C. A., Hall, L. S., et al. (2022) · Nature · doi:10.1038/s41586-022-04434-5 · Cited by 2,964 · see citing works
The subcellular organization of neocortical excitatory connections
Petreanu, L., Mao, T., Sternson, S. M., & Svoboda, K. (2009) · Nature · doi:10.1038/nature07709 · Cited by 1,047 · see citing works
Single-cell genomics identifies cell type–specific molecular changes in autism
Velmeshev, D., Schirmer, L., Jung, D., Haeussler, M., Perez, Y., Mayer, S., Bhaduri, A., Goyal, N., Rowitch, D. H., & Kriegstein, A. R. (2019) · Science · doi:10.1126/science.aav8130 · Cited by 927 · see citing works
SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs)
Abrahams, B. S., Arking, D. E., Campbell, D. B., Mefford, H. C., Morrow, E. M., Weiss, L. A., Menashe, I., Wadkins, T., Banerjee-Basu, S., & Packer, A. (2013) · Molecular Autism · doi:10.1186/2040-2392-4-36 · Cited by 873 · see citing works
Cell type- and brain region-resolved mouse brain proteome
Sharma, K., Schmitt, S., Bergner, C. G., Tyanova, S., Kannaiyan, N., Manrique-Hoyos, N., Kongi, K., Cantuti, L., Hanisch, U.-K., Philips, M.-A., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4160 · Cited by 871 · see citing works
Gerfen, C. R., Paletzki, R., & Heintz, N. (2013) · Neuron · doi:10.1016/j.neuron.2013.10.016 · Cited by 647 · see citing works
Classification of electrophysiological and morphological neuron types in the mouse visual cortex
Gouwens, N. W., Sorensen, S. A., Berg, J., Lee, C., Jarsky, T., Ting, J., Sunkin, S. M., Feng, D., Anastassiou, C. A., Barkan, E., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0417-0 · Cited by 456 · see citing works
Excitatory neuronal connectivity in the barrel cortex
Feldmeyer, D. (2012) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2012.00024 · Cited by 298 · see citing works
Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration
Molina-Gonzalez, I., Holloway, R. K., Jiwaji, Z., Dando, O., Kent, S. A., Emelianova, K., Lloyd, A. F., Forbes, L. H., Mahmood, A., Skripuletz, T., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39046-8 · Cited by 176 · see citing works
Self-citationA multiregional proteomic survey of the postnatal human brain
Carlyle, B. C., Kitchen, R. R., Kanyo, J. E., Voss, E. Z., Pletikos, M., Sousa, A. M. M., Lam, T. T., Gerstein, M. B., Sestan, N., & Nairn, A. C. (2017) · Nature Neuroscience · doi:10.1038/s41593-017-0011-2 · Cited by 143 · see citing works
Chuang, H.-C., Huang, T.-N., & Hsueh, Y.-P. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00280 · Cited by 56 · see citing works
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Kaulich, E., Waselenchuk, Q., Fürst, N., Desch, K., Mosbacher, J., Ciirdaeva, E., Juengling, M., Tushev, G., Langer, J., & Schuman, E. M. (2024) · doi:10.1101/2024.08.05.606570 · Cited by 22 · see citing works
- Authors
- Marcassa, G., Dascenco, D., Lorente-Echeverría, B., Daaboul, D., Vandensteen, J., Leysen, E., Baltussen, L., Howden, A. J. M., & de Wit, J.
- Affiliations
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- University of Dundee (GB)
- ORCID
- Venue
- Nature Communications
- Published
- 2025-01-02
- Volume
- 16
- Issue
- 1
- Pages
- 228-228
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11697078
- OpenAlex
- W4406001182
- Cited by
- 14
- References
- 13
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 1
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, cc-by-nc-nd)
- Lirias (submittedVersion, cc-by-nc-nd)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fonds Wetenschappelijk Onderzoek (11F1219N, G0C4518N, 11F1221N, G0H2818N)
- KU Leuven
- Vlaamse regering
- National Institute of Mental Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Biotin and Related Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- intratelencephalic neurons, pyramidal tract neurons, proximity biotinylation, autism risk genes, disease susceptibility, cell surface proteins, neurotransmitter receptors, ion channels
- MeSH terms
- Animals, Autistic Disorder, Female, Humans, Male, Membrane Proteins, Mice, Inbred C57BL, Synaptic Transmission, Pyramidal Tracts, Somatosensory Cortex, Synapses, Pyramidal Cells, Mice
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