Synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons
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 o...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55470-w |
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| author | Gabriele Marcassa Dan Dascenco Blanca Lorente-Echeverría Danie Daaboul Jeroen Vandensteen Elke Leysen Lucas Baltussen Andrew J. M. Howden Joris de Wit |
| author_facet | Gabriele Marcassa Dan Dascenco Blanca Lorente-Echeverría Danie Daaboul Jeroen Vandensteen Elke Leysen Lucas Baltussen Andrew J. M. Howden Joris de Wit |
| author_sort | Gabriele Marcassa |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-aad610b666d749578f44b947a594eed0 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-aad610b666d749578f44b947a594eed02025-01-05T12:38:54ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-024-55470-wSynaptic signatures and disease vulnerabilities of layer 5 pyramidal neuronsGabriele Marcassa0Dan Dascenco1Blanca Lorente-Echeverría2Danie Daaboul3Jeroen Vandensteen4Elke Leysen5Lucas Baltussen6Andrew J. M. Howden7Joris de Wit8VIB Center for Brain & Disease ResearchVIB Center for Brain & Disease ResearchVIB Center for Brain & Disease ResearchVIB Center for Brain & Disease ResearchVIB Center for Brain & Disease ResearchVIB Center for Brain & Disease ResearchVIB Center for Brain & Disease ResearchCell Signalling and Immunology, University of DundeeVIB Center for Brain & Disease ResearchAbstract 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.https://doi.org/10.1038/s41467-024-55470-w |
| spellingShingle | Gabriele Marcassa Dan Dascenco Blanca Lorente-Echeverría Danie Daaboul Jeroen Vandensteen Elke Leysen Lucas Baltussen Andrew J. M. Howden Joris de Wit Synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons Nature Communications |
| title | Synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons |
| title_full | Synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons |
| title_fullStr | Synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons |
| title_full_unstemmed | Synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons |
| title_short | Synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons |
| title_sort | synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons |
| url | https://doi.org/10.1038/s41467-024-55470-w |
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