Homeostatic regulation of neuronal activity involves a wide range of both network-adaptive and cell-autonomous mechanisms. Among the latter, structural plasticity at the axon initial segment (AIS) has been recently described to regulate axonal excitability through the modulation of its position and length (Grubb & Burrone, 2010). Thus, altering neuronal activity correlates with structural changes in the AIS, such as its length or distance from the soma. These structural modifications, accompanied by modulation of the ion channel repertoire, modify the biophysical properties of the AIS (Grubb & Burrone, 2010; Evans et al., 2015; Kuba et al., 2015). These modifications can decouple the output of a hyper-excited circuit in a negative feedback loop or conversely, enhance the output of a silent network. These observations have extended the role of the AIS beyond the maintenance of neural polarity and the propagation of nervous impulse through its protein sorting action and facilitation of action potential initiation. However, the core mechanisms involved in AIS structural plasticity have remained unclear.