Adaptations of the axon initial segment in fast-spiking interneurons of the human neocortex support low action potential thresholds

The mammalian brain exhibits notable interspecies variation. Microanatomical and molecular differences in homologous neurons, those with similar locations and developmental origins across species, are best characterized in the neocortical mantle, the center of complex brain functions; however, the purpose of these differences remains unclear. We performed whole-cell microelectrode recordings along with microanatomical and molecular analyses of human fast-spiking parvalbumin (pvalb)-expressing interneurons in neocortical tissue resected during brain surgery, comparing them with similar data obtained from the mouse neocortex. The action potential (AP) firing threshold was lower in human neurons than in mouse neurons. This was due to a deficiency in low-voltage–activated inhibitory Kv1.1 and Kv1.2 potassium channels in the axon initial segment (AIS), a specialized axonal region that determines AP threshold and initiation, in human cells. In contrast, Kv1 ion channels were prominent in mouse neurons. The AIS was also moderately elongated in humans. Computational simulations of fast-spiking interneurons revealed that the human-type AIS lowers the AP threshold and shortens the time lag for AP initiation. We found that the low membrane AP firing threshold in pvalb neurons is closely linked to slow membrane potential kinetics in the soma. Thus, the human AIS supports fast in–fast out circuit function in human pvalb neurons, compensating for electrically slow somatic membrane responses. When formulating therapeutic strategies that involve fast-spiking neurons, it is crucial to take into account the molecular and functional species differences.