Mechanisms and purpose of lowered action potential firing threshold in fast-spiking interneurons in the human neocortex

The mammalian brain exhibits various interspecies differences. Microanatomical and molecular differences in homologous neurons between species are best characterized in the neocortical mantle, but the purpose of these differences remains poorly understood. We performed whole-cell microelectrode recordings and microanatomical and molecular analyses of human fast-spiking parvalbumin (pvalb)-expressing interneurons in neocortical tissue resected during brain surgery. Fast-spiking interneurons exhibited a lower action potential (AP) firing threshold in humans than in mice. Compared with mouse neurons, human neurons displayed an elongated axon initial segment (AIS), and the human AIS was deficient in low-voltage activated inhibitory Kv1 potassium channels. Contrarily, Kv1 ion channels were prominent in mouse neurons. Computational fast-spiking interneuron model simulations revealed that human-type AIS lowers the AP threshold and shortens the time lag for AP generation. Thus, human AIS supports fast in–fast out electrical circuit function in human pvalb neurons, which have electrically slow membrane potential kinetics in somata.