Hence, the AIS is also an energetically favorable site for AP initiation. Furthermore, the small capacitance of the AIS favors rapid changes in membrane potential, as occurs during the upstroke of PF2341066 the AP (dV/dt = I/C). Finally, it is worth noting that having a single site of AP generation
provides neurons a single locus where inhibition can gate AP initiation. One of the consequences of initiation of APs in the AIS, followed by backpropagation to the soma, is that from a somatic point of view the temporal relationship between synaptic input and AP initiation is distorted. As a result AP threshold is more depolarized at the soma than in the AIS (Kole and Stuart, 2008), and somatic AP threshold shows increased variability compared to that in the AIS (Yu et al., 2008). The geometry of the AIS DAPT concentration (degree of taper and diameter), as well as the location, density, and properties of Na+ channel in the AIS, influences the capacity of APs
initiated in the AIS to propagate back to the soma (Hu et al., 2009, Mainen et al., 1995 and Moore et al., 1983). It might be expected, therefore, that the location of Na+ channels in AIS will influence somatic AP voltage threshold. Consistent with this, the location of Na+ channels in the AIS is thought to underlie differences in somatic AP threshold between hippocampal dentate granule and CA3 pyramidal neurons (Kress et al., 2010). The precise location and density of Na+ channels in the AIS can also influence the fidelity of AP 4-Aminobutyrate aminotransferase initiation. Initiation of APs further from the soma, taking advantage of the electrical isolation of this region, is a strategy used in some neurons to increase their capacity to discriminate the arrival time of different synaptic inputs. In neuronal pathways associated with hearing this helps determination
of interaural timing differences (ITD). In nuclueus laminaris (NL) neurons in birds the distance of the AIS from the soma, as well as its length, depends on the characteristic frequency of presynaptic inputs the neuron receives (Kuba et al., 2006 and Kuba and Ohmori, 2009). Na+ channels in the AIS are located more distally from the soma in neurons that have high characteristic frequencies (>2 kHz) compared to neurons tuned to low characteristic frequencies (≤1 kHz). Modeling indicates that the more distal location of the AIS in neurons that received inputs with high characteristic frequencies increases their capacity to detect ITDs. This occurred for two reasons. First, the passive cell body of NL neurons acts as a leak decreasing the membrane time constant and reducing the filtering of synaptic input frequencies (Ashida et al., 2007). Second, the distal position of Na+ channels in the AIS reduces steady-state inactivation, increasing the number of Na+ channels available for activation (Kuba et al., 2006).