, 1968 and Peters et al., 1968). While the molecular composition of this granular layer is not fully understood, by analogy with nodes of Ranvier it is thought to contain a high density of voltage-gated channels together with specialized anchoring proteins important for action potential generation. In addition, the AIS of some neuronal cell types, such as cortical pyramidal neurons, receives

synaptic input (Figure 1) (Somogyi et al., 1998). Experiments in the 1950s proposed that action potentials (APs) are initiated in the proximal axon, at either the axon hillock (Fuortes et al., 1957) or the initial segment (Araki and Otani, 1955 and Coombs et al., 1957). Aided by advances in electrical and optical recording techniques, recent data have provided direct evidence in support of these early observations,

showing that APs are initiated at the distal end of the AIS Bioactive Compound Library in a large range of neuronal cell types. These studies have in addition revealed that the AIS is not just a trigger zone for AP generation, but also plays a key role in regulating the integration Pexidartinib order of synaptic input, as well as intrinsic excitability and transmitter release. In this review we focus on the detailed electrical properties of the AIS and describe how these unique properties influence synaptic integration and shape neuronal output. We refer the reader to excellent recent reviews on the physiology of the axon proper and the molecular structure of the AIS (Debanne et al., 2011 and Rasband, 2010). While it why has long been thought that APs are initiated in the AIS of neurons in the mammalian CNS, this is not the case in all species. For instance, multipipette recording and voltage-sensitive dye imaging indicate that AP initiation in invertebrate neurons can occur at multiple locations, which can act independently (Calabrese

and Kennedy, 1974, Maratou and Theophilidis, 2000, Meyrand et al., 1992, Tauc, 1962 and Zecević, 1996). These studies indicate that invertebrate neurons lack the functional polarization found in neurons of the mammalian CNS (Rasband, 2010). It is therefore relevant to ask why and when in evolution did neurons develop an AIS, thereby defining a single locus for AP generation? Insights into the evolution of the AIS have been obtained by studying the gene sequences of Na+ and K+ channels, which are localized to the AIS via an interaction with the cytoskeletal scaffolding protein Ankyrin G. Ankyrin G, widely used as a marker for the AIS, is restricted in expression to the AIS and nodes of Ranvier and required for targeting of voltage-gated Na+ channels to the AIS (Kordeli et al., 1995 and Zhou et al., 1998). This occurs via an interaction between Ankyrin G and a conserved nine amino acid sequence in the II-III domain of Na+ channels (Garrido et al., 2003).