The new code… Neurons communicate through electrical signals and diffusible chemicals. Yet, the code governing how they connect is still poorly understood.  Here, the authors tested the bold idea that connectivity patterns may be predicted by physical interactions between neurons, specifically through ligand–receptor (LR) binding. They found that, indeed, specific LR combinations strongly predicted connectivity in the sensory cortex. However, these interactions rarely acted alone as wiring patterns were best explained by combinations of both rare and common LR pairs. This offers a new clue as to how networks are built.

The authors: R Mathieu, T Draia-Nicolau, L Corbières, A Govindan, V Bensa, E Pallesi-Pocachard, L Silvagnoli, A Represa, C Cardoso, L Telley, A de Chevigny

Scientific 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.

Published in Nature Communications, 2026

All datasets, analyses, and interactive graphs are available here: https://github.com/Cortical-interactome/scLRSomatoDev