Functional KCC2 expression marks an evolutionarily conserved population of early-maturing interneurons in the perinatal cortex

Abstract

The developmental shift from depolarizing to hyperpolarizing GABA responses is a pivotal step in the maturation of GABAergic transmission and cortical circuits; classically documented in principal neurons during the first postnatal week in the mouse cortex. Surprisingly, whether maturation of GABA-mediated responses follows the same temporal pattern in cortical interneurons (INs) remains unresolved. Leveraging an array of methods, a high-resolution cortical development mouse atlas and single-cell RNA sequencing, we identify and comprehensively characterize a population of early-maturing cortical INs in mice, distinguished by KCC2 expression at embryonic stages and concomitant hyperpolarizing GABA_A responses at birth. These early KCC2-expressing INs exhibit precocious intrinsic excitability, synaptic integration, and dendritic complexity at birth, contrasting delayed maturation in principal neurons and other INs. Spatial transcriptomics and differential gene expression (DGE) analyses reveal early KCC2-expressing INs localize predominantly to layer 5, express somatostatin, and show upregulation of synaptogenic genes, consistent with the recorded elevated synaptic activity. Crucially, evolutionary conservation of early KCC2-expressing INs in humans was demonstrated with analogous genetic profiles enriched for signaling and synaptic maturation pathways. This work resolves a critical gap in developmental neurobiology, demonstrating heterogenous GABAergic functional maturation within IN subpopulations and establishing KCC2 as a marker of early-maturing INs.

Affiliated Institutions

• University of Helsinki FI
• Institut de Neurobiologie de la Méditerranée FR
• Inserm FR
• Aix-Marseille Université FR

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