Synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons

Gabriele Marcassa, Dan Dascenco, Blanca Lorente-Echeverría, Danie Daaboul, Jeroen Vandensteen, Elke Leysen, Lucas Baltussen, Andrew J. M. Howden and Joris Wit ()
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Gabriele Marcassa: VIB Center for Brain & Disease Research
Dan Dascenco: VIB Center for Brain & Disease Research
Blanca Lorente-Echeverría: VIB Center for Brain & Disease Research
Danie Daaboul: VIB Center for Brain & Disease Research
Jeroen Vandensteen: VIB Center for Brain & Disease Research
Elke Leysen: VIB Center for Brain & Disease Research
Lucas Baltussen: VIB Center for Brain & Disease Research
Andrew J. M. Howden: University of Dundee
Joris Wit: VIB Center for Brain & Disease Research

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55470-w

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