Conserved Kir channel mechanisms governing intrinsic excitability in human and rodent parvalbumin neurons

Abstract Human cortical interneurons differ from their rodent counterparts in intrinsic membrane properties, yet the mechanisms regulating excitability across physiologically relevant membrane potentials remain poorly defined. Here, we investigated inwardly rectifying potassium (Kir) channel control of subthreshold excitability in parvalbumin-expressing (Pvalb) interneurons from human and mouse neocortex. Using whole-cell recordings, dynamic clamp, patch sequencing, immunofluorescence, and computational modeling, we show that membrane hyperpolarization induces a proportional decrease in input resistance mediated by Kir channels in both species, despite higher baseline input resistance in human neurons. Transcriptomic and anatomical analyses revealed somatic membrane expression of four major Kir channel subtypes with moderate interspecies differences. Kir activation suppresses intrinsic excitability through combined voltage-dependent and shunting inhibition, an effect occurring during inhibitory postsynaptic potentials evoked by neurogliaform cells. Together, these findings show that homologous Pvalb neurons in humans have evolved toward a conserved, archetypal excitability phenotype, despite substantial differences in baseline excitability between species.