TY - JOUR
T1 - Synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons
AU - Marcassa, Gabriele
AU - Dascenco, Dan
AU - Lorente-Echeverría, Blanca
AU - Daaboul, Danie
AU - Vandensteen, Jeroen
AU - Leysen, Elke
AU - Baltussen, Lucas
AU - Howden, Andrew J. M.
AU - de Wit, Joris
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2025/1/2
Y1 - 2025/1/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85213863790&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-55470-w
DO - 10.1038/s41467-024-55470-w
M3 - Article
C2 - 39747884
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
M1 - 228
ER -