Glucose increases the length and spacing of the lattice structure of the axon initial segment

The axon initial segment (AIS) plays an important role in maintaining neuronal polarity and initiating action potentials (APs). The AIS adapts to its environment by changing its length and distance from the cell body, resulting in modulation of neuronal excitability, which is referred to as AIS plasticity. Previous studies found an ~200 nm single periodic distribution of the key AIS components ankyrinG (AnkG), Na_v 1.2, and βIV-spectrin, while it remains unclear how the lattice structure is altered by AIS plasticity. In this study, we found that the length of the AIS significantly increased, resulting in increased neuronal excitability, with high-concentration glucose treatment. Structured illumination microscopy (SIM) images of the lattice structure showed a dual-spacing periodic distribution (~200 nm and ~260 nm) of AnkG, Na_v 1.2, and βIV-spectrin. Moreover, 480-kDa AnkG was crucial for AIS plasticity and increased lattice structure spacing. The discovery of new regulators for modulating AIS plasticity will help us to understand and manipulate the structure and function of the AIS. Glucose triggers axon initial segment (AIS) plasticity of cultured neurons. AIS lattice structure under glucose treatment shows an increased spacing by structured illumination microscopy imaging. 480-kDa AnkG contributes to AIS plasticity.