Inferring Ligand-Receptor Interactions between neuronal subtypes during mouse cortical development

Abstract

The cerebral cortex hosts a diverse array of excitatory glutamatergic and inhibitory GABAergic neuron types, each characterized by distinct positional and synaptic connectivity patterns. However, the molecular mechanisms orchestrating this precise organization remain largely unknown. To identify ligand-receptor (LR) pairs regulating interactions and connectivity among cortical neurons during embryonic and postnatal development, we analyzed the transcriptional dynamics of all genes across major cortical neuron subtypes at 17 developmental time points using single-cell transcriptomics. From these data, we constructed a comprehensive bioinformatic atlas that inferred significant LR-mediated interactions between glutamatergic and GABAergic neurons throughout cortical maturation. This atlas not only corroborated known interactions but also enabled the discovery of novel regulators, identifying two cadherin superfamily members as key mediators of perisomatic inhibition in deep and superficial layer excitatory neurons by parvalbumin-expressing basket cells. These findings underscore the power of large-scale transcriptional profiling to unravel fundamental molecular mechanisms driving cortical circuit assembly.