The dynamic axon initial segment: From neuronal polarity to network homeostasis

The axon initial segment (AIS) is a highly specialized compartment in neurons that resides in between axonal and somatodendritic domains. The localization of the AIS in the proximal part of the axon is essential for its two major functions: generating and modulating action potentials and maintaining neuron polarity. Recent findings revealed that the incredibly stable AIS is generated from highly dynamic components and can undergo extensive structural and functional changes in response to alterations in activity levels. These activity-dependent alterations of AIS structure and function have profound consequences for neuronal functioning, and AIS plasticity has emerged as a key regulator of network homeostasis. This review highlights the functions of the AIS, its architecture, and how its organization and remodeling are influenced by developmental plasticity and both acute and chronic adaptations. It also discusses the mechanisms underlying these processes and explores how dysregulated AIS plasticity may contribute to brain disorders.