The Latest on the Axon Initial Segment

This paper will review the latest results about the axon initial segment (AIS) revealing physiology details while focusing on the structural organization of the AIS. This highly specialized region of the axon is characterized, among others, by high concentrations of (particular) voltage-gated ion channels, and by highly specialized cytoskeletal networks. These repetitive and regular tiny structures (down to molecular motifs) act in synch for maintaining and modifying the functionalities associated to AIS: action potential initiation, threshold modulation, activity-dependent plasticity, assembly and maintenance, diffusion barrier (bi-directional selective filtering), etc. Significant progress in our understanding of the structural organization of the AIS has developed rapidly in recent years based on advances in high-resolution microscopy. Still, the precise ways through which the regular tiny structures observed are affecting functioning need significantly more effort. As an example here, one can look at the different voltage-gated ion channels and at their positioning, which are affecting the triggering of the action potential. When their variable densities are taken in conjunction with the regular spacing induced by the cytoskeleton, one cannot help but wonder about concepts akin to distributed amplification which have never been put forward before in this biological context. That is why we conclude with quite a few open questions.