Axon Initial Segment: Structure, Biological Functions, Diseases, and Therapeutic Targets

Abstract

The axon initial segment (AIS) is a specialized neuronal microdomain that serves as a physical diffusion barrier, separating the axon from somatodendritic compartments. As a highly plastic structure, the AIS dynamically regulates neuronal excitability and contributes to circuit homeostasis. Recent advances in super-resolution imaging and disease modeling have expanded our understanding of its role in neurodevelopment and neurodegenerative disorders. This review first systematically outlines the molecular architecture of the AIS, including its cytoskeletal scaffolds and ion-channel complexes. Then, we discuss AIS plasticity, ranging from activity-dependent alterations to the molecular mechanisms that regulate it, and to its key biological functions, such as its role in action potential initiation, neuronal polarization, subcellular organelle sorting, and neural circuit excitability. We further highlight emerging evidence that AIS disruption represents an early pathological event in neurodegenerative and neuropsychiatric disorders. By integrating physiological and pathological perspectives, and by evaluating emerging biomarker strategies and therapeutic interventions, this review outlines directions and challenges for future AIS-targeted therapies. Meanwhile, it summarizes key experimental and potential clinical tools for future AIS research. Overall, elucidating the molecular mechanism of the AIS in both health and disease provides a deeper understanding for advancing the diagnosis and treatment of neurological diseases.

Keywords

axon initial segment / action potential / neural circuit / neurological disorders / plasticity

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