Decoding Cortical Circuits: Synaptic Signatures and Disease Vulnerabilities of Layer 5 Pyramidal Neuron Types

Cortical layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons are embedded in distinct information processing pathways. Despite their significance for cognitive function, it remains poorly understood how L5 neuron types are connected into circuits and how this might be perturbed in disease. Utilizing an optimized proximity biotinylation workflow, we characterize the excitatory postsynaptic proteomes of L5 IT and PT neurons in intact somatosensory circuits. We find distinct molecular synaptic signatures of L5 IT and PT neurons defined by proteins regulating synaptic transmission and organization, suggesting that these contribute to function and input connectivity of L5 neuron types. The synaptic signature of L5 IT, but not of PT, neurons displays a marked enrichment of autism risk genes, aligning with previous studies highlighting the vulnerability of IT neurons and suggesting that the excitatory postsynaptic compartment of L5 IT neurons is notably susceptible in autism. Our analysis sheds light on the proteins that govern circuit integration and function of L5 neuron types and underlie their susceptibility in disease. Moreover, our approach is broadly applicable to other neuron types and circuits. ### Competing Interest Statement The authors have declared no competing interest.