, 1993). Although INaP remains to be measured in cortical mammalian nodes, noninactivating channel openings underlying INaP have been directly recorded in the frog node BMS-387032 price of Ranvier ( Dubois and Bergman, 1975). What makes the node prone to generating persistent Na+ current? Although the precise molecular basis of persistent Na+ current is still elusive, the steady current flow most likely reflects a gating mode of the conventional Na+ channel. In the model of Taddese and Bean (2002), persistent and transient Na+ currents could be explained by a single Na+ channel,

assuming that the inactivating particle binds weakly to Na+ channels in the resting inactivated state but strongly to already activated channels. This scheme predicts larger INaP

when more Na+ channels are in the resting condition, when inactivation Cobimetinib in vivo is incomplete and weak and membrane densities are high. Large axonal INaP might be a simple consequence of the high density and the specific gating properties of the axonal Na+ channel isoform. First, compared to the soma, the voltage dependence of activation and inactivation of axonal Na+ current is shifted 10 mV to more hyperpolarized potentials, and consequently, a larger fraction of Na+ channels are in the resting inactivated state ( Kole et al., 2008 and Schmidt-Hieber and Bischofberger, 2010). Second, Nav1.6, which is the main isoform in adult myelinated axons ( Boiko et al., 2001 and Lorincz and Nusser, 2010), is in particular prone to entering a noninactivating state ( Rush et al., 2005). Finally, recent estimations suggest that nodes of Ranvier express Nav1.6 at even higher densities compared to the AIS ( Lorincz learn more and

Nusser, 2010). How does a subthreshold current in the node influence excitability in the AIS? The AIS and first node are separated by a single ∼50–100 μm long internodal and myelinated section, suggesting a tight electrotonic coupling. This idea is supported by whole-cell recordings showing that steady-state voltage attenuation in the first ∼150 μm of the axon is small (<10%, Kole et al., 2007). During ongoing synaptic activity, the first node may be activated with voltage fluctuations nearly similar to the AIS, placing the first node in a strategic position to integrate synaptic inputs and modulate output generated in the AIS. A steady inward current near the site of AP initiation could effectively reduce the electrical load of the first internodal section, leading to a more hyperpolarized axosomatic AP voltage threshold. Based on the somatically recorded INaP, axons cut before the branchpoint had an ∼250 pA reduced persistent current at −50 mV ( Figure 6). Given an average input resistance of 20 MΩ, the reduced INaP may thus fully account for the ∼5 mV (ΔV = ΔI × R) more depolarized AP voltage threshold observed during steady depolarizations.