# Cortical Neurons Adjust the Action Potential Onset Features as a Function of Stimulus Type
## 4 Discussion  
We examined whether RS and FS somatosensory cortical neurons adjusted their AP shape in response to different stimulus types. We demonstrated that cortical neurons differentiate between stimulus types through their evoked AP shape. However, the difference in AP shape was more apparent in pyramidal RS neurons than in FS neurons. Interestingly, the resulting AP onset parameters from the two stimulation types were significantly different only in RS neurons. The average rapidity increased from 3.97 ms\({}^{-1}\) for step-and-hold stimulation to 5.41 ms\({}^{-1}\) for frozen noise stimulation. However, FS cortical neurons responded stereotypically regardless of the input stimulus (6.40 ms\({}^{-1}\) for step-and-hold current and 6.33 ms\({}^{-1}\) for frozen noise current). Furthermore, we found that AP onset dynamics were more variable in RS than in FS neurons. Synaptic-like stimulus (frozen noise) increased threshold variability in RS neurons by approximately 87%, while threshold variability was minimal for FS neurons regardless of the stimulus type (11% difference). These results suggest that the interplay of Na_v 1.2 and Na_v 1.6, among other factors, may encode the difference in stimulus by adjusting their activation mechanism. Threshold variability and rapid AP onset are characteristics of cortical neurons. These two unique features can be attributed to several mechanisms. AP backpropagation from the spike initiation site at the AIS to the soma can distort the somatic AP, causing the onset dynamic to become highly variable and rapid compared to AIS AP [15]. Hence, a shift in the AP initiation site can influence AP onset parameters. Several studies have shown that the AIS adapts its length or shifts the AP initiation site after repetitive firing [26; 27; 28]. Thus, a shift in the AP initiation site may affect AP onset parameters in somatic recordings. However, while this shift can influence the somatic AP onset dynamics, AP backpropagation cannot adequately reproduce the observed AP onset dynamics [17; 29]. An alternative explanation for the rapid and variable AP onset in mammalian neurons is due to neuron geometry: more precisely, the resistive coupling theory [17; 30; 31]. The differences in size and the small distance between the soma and AIS cause the sharp somatic AP onset and threshold variations observed in the soma of mammalian neurons [17; 32]. Thus, the resistive coupling theory may explain the significant difference in AP rapidity between RS and FS cortical neurons, since the two neuron types have different geometry. If the AP initiation site shifts due to repetitive firing, the coupling resistivity between the soma and AIS may explain the increase in AP rapidity in the same RS neurons due to repetitive stimulation. The shift in the AP initiation site may be attributed to the inactivation of axonal sodium channels due to somatic depolarization spreading into the axon, occurring on a tenth-of-a-millisecond time scale [28]. Another explanation for the observed AP initiation properties was associated with the expression of multiple voltage-gated channels or their gating mechanism. Cooperative gating between sodium channels was suggested to reproduce the sharp AP onset and variability in modeling studies [16; 33], which was supported by recent evidence in cardiac Na_v1.5 [34; 35; 36; 37]. On the other hand, changes in resting potential could influence neuronal excitability and hence the AP shape. For instance, difference in resting potential between the soma and axon was observed in the cortical layer 5 pyramidal neuron, due to the differences in voltage-gated channels (such as Na_v, K_v, Ca_v, and HCN) between the two neuronal compartments [38], and the interaction among the different channels can influence the AP shape [39]. However, further investigation is needed to show whether the AP initiation site shifts between the two stimuli, a difference in voltage-gated channels expression, or cooperative gating could explain the observed results.