Uncovering the molecular logic of cortical wiring between neuronal subtypes across development through ligand-receptor inference.

Abstract

The cerebral cortex comprises diverse excitatory and inhibitory neuron subtypes, each with distinct laminar positions and connectivity patterns. Yet, the molecular logic underlying their precise wiring remains poorly understood. To identify ligand-receptor (LR) interactions involved in cortical circuit assembly, we tracked gene expression dynamics in mice across major neuronal populations at 17 developmental stages using single-cell transcriptomics. This generated a comprehensive atlas of LR-mediated communication between excitatory and inhibitory neuron subtypes, capturing known and novel interactions. Notably, we identified NEOGENIN-1 as the principal receptor for CBLN4 during the perinatal period, mediating synapse formation between somatostatin-expressing interneurons and glutamatergic neurons. We also identified members of the cadherin superfamily as candidate regulators of perisomatic inhibition from parvalbumin-expressing basket cells onto deep and superficial excitatory neurons, exerting opposing effects on synapse formation. These findings suggest a context-dependent role for cadherins in synaptic specificity and underscore the power of single-cell transcriptomics for decoding the molecular mechanisms of cortical wiring.