Nav1.2 and BK channels interaction shapes the action potential in the axon initial segment

In neocortical layer-5 pyramidal neurons, the action potential (AP) is generated in the axon initial segment (AIS) when the membrane potential (V _m ) reaches the threshold for activation of two diverse voltage-gated Na ⁺ channels, that differ in spatial distribution and biophysical properties. Yet, the understanding of specific functional differences between these two channels remains elusive. Here, using ultrafast Na ⁺ , V _m and Ca ²⁺ imaging in combination with partial block of Na _v 1.2 by a recent peptide, we demonstrate an exclusive role of Na _v 1.2 in shaping the generating AP. Precisely, Ca ²⁺ influx via Na _v 1.2 activates BK Ca ²⁺ -activated K ⁺ channels determining the amplitude and the early phase of repolarisation of the AP in the AIS. We mimicked this result with a NEURON model where the role of the different ion channels tested reproduced the experimental evidence. The exclusive role of Na _v 1.2 reported here is important for understanding the physiology and pathology of neuronal excitability.