NM neurons that receive

a large number of small inputs had higher AIS Na+ channel densities, improving AP precision, whereas NM neurons that receive a smaller number of large inputs had lower AIS Na+ channel densites. Voltage-gated K+ channels in the AIS also play an important role in regulation PLX4032 clinical trial AP firing. In pyramidal neurons Kv1 channels, generating D-type current, have been shown to delay the onset of AP firing in response to sustained depolarisation (Storm, 1988), as well as influence AP threshold and interspike interval (Bekkers and Delaney, 2001 and Goldberg et al., 2008), whereas Kv7 channels influence spike-frequency adaptation, subthreshold resonance, and both spontaneous and AP burst firing (Hu et al., 2007, Peters et al., 2005, Shah et al., 2008 and Yue

and Yaari, 2004). Kv1 channels are the main K+ channel involved in regulating AP half-width in the AIS and the axon proper (Figure 4A) (Kole et al., 2007 and Shu et al., 2007b). With increasing distance from the soma the axonal AP half-width decreases steeply in parallel with an increase in the afterhyperpolarization (Kole et al., 2007). As a result, in cortical pyramidal neurons the AP half-width is ∼250 μs at the distal end of the AIS, similar to that of APs recorded in axonal boutons (Alle and Geiger, 2006 and Alle aminophylline et al., 2009). Keeping the AP in the AIS brief is likely to be crucial for enabling selleck screening library rapid recovery of Na+ channels from inactivation, consistent with the absence of AP failures in the AIS even at high frequencies (Popovic et al., 2011). More recent work indicates that calcium influx through AIS voltage-gated Ca2+ channels (Figure 4B) can activate calcium-activated K+ channels in the AIS of pyramidal neurons in ferret prefrontal cortex (Figure 4C) (Yu et al., 2010), providing an additional means to regulate axonal AP repolarization. Whether this observation can be extended to the AIS of other neuronal cell types remains to be tested. Together, these

data indicate that K+ channels in the AIS play a critical role in regulating axonal AP width and thereby the AP firing pattern in response to synaptic input. Recent observations also indicate that ion channels in the AIS can be modulated by neurotransmitters, thereby influencing AP firing patterns. This has been investigated in glycinergic brain stem interneurons, called cartwheel cells, where T-type Ca2+ channels in the AIS are selectively inhibited by dopamine, via a protein kinase C pathway (Figures 5A and 5B) (Bender et al., 2010). As a result the mode of spontaneous AP firing is converted from high-frequency bursts to tonic firing (Figures 5C and 5D) (Bender et al., 2012).