SST interneuron maturation extends beyond the second postnatal week and is driven by coordinated transcriptional and functional remodeling.

Abstract

Cortical somatostatin-expressing (SST+) interneurons (cINs) are key regulators of dendritic integration and synaptic plasticity, yet the timing and molecular mechanisms underlying their postnatal maturation remain incompletely understood. Previous studies have suggested that key aspects of SST+ cIN maturation are largely established by the end of the second postnatal week. Here, we combined transcriptomic profiling and electrophysiological recordings to characterize the developmental trajectory of SST+ interneurons in the mouse neocortex from the second postnatal week through the end of the first postnatal month. Bulk RNA sequencing of fluorescence-activated cell sorted SST+ cINs at P10, P15, and P30 revealed extensive transcriptional remodeling, including continued upregulation of genes associated with ion channel activity, synaptic transmission, and neuronal excitability beyond the second postnatal week. Consistent with these molecular changes, electrophysiological recordings demonstrated ongoing maturation of intrinsic and synaptic properties between P15 and P30. Notably, developmental upregulation of voltage-gated sodium and potassium genes correlated with the observed changes in intrinsic excitability, while alterations in GABA _A receptor subunit expression paralleled the maturation of inhibitory synaptic transmission. Computational modeling incorporating these transcriptional changes recapitulated the electrophysiological differences between P15 and P30 SST+ cINs. Together, our findings demonstrate that SST+ cIN maturation is not complete by the second postnatal week but instead continues through later postnatal stages, revealing a prolonged and coordinated transcriptional and physiological program underlying their functional integration into cortical circuits.