Accurate determinations of Na+ channel distributions require unbiased matching of a wide range of AP properties (amplitude, rate of rise, site of initiation) in morphological realistic models. Using this approach, estimates in large cortical pyramidal neurons indicate AIS-to-soma Na+ channel ratios of ∼50-fold (Kole et al., 2008), whereas in electronically compact dentate granule cells a ∼5-fold difference seems to suffice (Schmidt-Hieber and Bischofberger, 2010). In addition to their high density, the properties of Na+ channels PFI-2 order in the AIS are specialized, presumably to facilitate AP initiation in the AIS. For example, the voltage dependence of both activation and inactivation of AIS

Na+ channels is hyperpolarized by ∼10mV compared to Na+ channels at the soma (Figure 2C) (Colbert and Pan, 2002, Hu et al., 2009 and Kole et al., 2008). This observation is consistent with subunit-specific differences in the voltage dependence of Na+ channels (Rush et al., 2005), providing further evidence that the primary Na+ channel subunit in the AIS is Nav1.6

(Hu et al., 2009, Lorincz and Nusser, 2010 and Royeck et al., 2008). AIS Na+ channels in dentate granule cells have also been shown to activate and inactivate approximately two times faster than those at the soma (Schmidt-Hieber and Bischofberger, 2010). This observation VX 809 has been used to explain how a low density of Na+ channels in the AIS of cortical pyramidal neurons could generate fast rising APs in the AIS (Fleidervish et al., 2010). Faster channel kinetics, however, means less charge influx per channel, leading to smaller AP amplitudes for a given Na+ channel density. Rapid Na+ channel kinetics alone, therefore, is unlikely to explain AP generation in the AIS, leading to the conclusion that a high density of Na+ channels is likely to be an absolute requirement. Another specialized property of Na+ channels is that they Edoxaban can be activated at subthreshold potentials, as well as undergo incomplete inactivation, leading to generation of the so-called

persistent Na+ current (INaP) ( Taddese and Bean, 2002). Presumably due to the high density of Na+ channels in the AIS, INaP has been found to be greatest in the axon ( Astman et al., 2006 and Stuart and Sakmann, 1995), where it has a significant influence on AP threshold ( Kole and Stuart, 2008 and Royeck et al., 2008). Activation of INaP is also thought to be important for generation of the AP afterdepolarization, and as such plays a role in the generation of high-frequency AP bursts ( Azouz et al., 1996). Recent data in cortical pyramidal neurons indicates that AP bursts also require INaP activation at the first node of Ranvier ( Kole, 2011). Na+ channels, and especially the Nav1.6 isoform, can also undergo transient reactivation upon repolarization, leading to generation of a resurgent Na+ current (INaR).