, 1957). Although there is some experimental

evidence for AP initiation in the node (Clark et al., 2005 and Colbert and Johnston, 1996), more recent electrophysiological investigations showed that the AIS initiates all APs, and the first node faithfully follows spike frequencies with a ∼100 μs delay (Foust et al., 2010, Khaliq and Raman, 2006, Doxorubicin mouse Palmer et al., 2010 and Palmer and Stuart, 2006). It remains an open question whether the first node can influence the generation of APs. In mechanosensory leech axons, a direct role of branchpoints to neural computation has been demonstrated by a facilitation of transmitter release after the AP fails at a Depsipeptide molecular weight branchpoint and subsequently propagates in both reverse and forward directions (Baccus, 1998 and Debanne et al., 2011). Also, in mammalian axons there is evidence that the strategic placing of Na+ channels at axonal branchpoints exerts computational roles by counteracting impedance mismatches when APs invade

daughter collaterals at axonal bifurcations and thereby increase the safety factor for high-frequency spike propagation toward the presynaptic terminals (Goldstein and Rall, 1974, Khaliq and Raman, 2006, Manor et al., 1991 and Monsivais et al., 2005). To address whether the first node in mammalian axons plays a role in the input-output function, electrophysiological recordings of rat neocortical L5 neurons were made in combination with targeted inactivation of visually identified nodes. The results show that the over first node facilitates the initiation

of APs in the AIS selectively during high-frequency bursts (≥100 Hz). Inactivation of nodal Na+ channels demonstrated that the first node generates a TTX-sensitive persistent Na+ current, which lowers the axosomatic AP voltage threshold and amplifies the afterdepolarization (ADP). These results unveil a role for the first node of Ranvier in the temporal encoding of synaptic inputs into high-frequency APs in axons. Branchpoints in neocortical axons contain ultrastructural markers of nodes (Khattab, 1968 and Sloper and Powell, 1979). Furthermore, previous work showed that the first branchpoint in rodent L5 axons is physiologically characterized by AP-mediated Na+ influx and acts as an acceleration point in the saltatory propagation of APs (Fleidervish et al., 2010 and Palmer and Stuart, 2006). In the present study, it is therefore assumed that the first node is localized at the first branchpoint of the primary axon. To obtain detailed insight into the location and geometrical properties of the branchpoint, whole-cell patch-clamp recordings were made from large L5 pyramidal neurons in parasagittal slices in combination with two-photon laser scanning microscopy (n = 13) or post hoc biocytin staining (n = 9).