Abstract
The 20–60 μm axon initial segment (AIS) is proximally located at the interface between the axon and cell body. AIS has characteristic molecular and structural properties regulated by the crucial protein, ankyrin-G. The AIS contains a high density of Na+ channels relative to the cell body, which allows low thresholds for the initiation of action potential (AP). Molecular and physiological studies have shown that the AIS is also a key domain for the control of neuronal excitability by homeostatic mechanisms. The AIS has high plasticity in normal developmental processes and pathological activities, such as injury, neurodegeneration, and neurodevelopmental disorders (NDDs). In the first half of this review, we provide an overview of the molecular, structural, and ion-channel characteristics of AIS, AIS regulation through axo-axonic synapses, and axo−glial interactions. In the second half, to understand the relationship between NDDs and AIS, we discuss the activity-dependent plasticity of AIS, the human mutation of AIS regulatory genes, and the pathophysiological role of an abnormal AIS in NDD model animals and patients. We propose that the AIS may provide a potentially valuable structural biomarker in response to abnormal network activity in vivo as well as a new treatment concept at the neural circuit level.
Highlights
A 2019 study by Vassilopoulos et al unroofed the dorsal part of cultured neurons and used platinum replica electron microscopy (PREM) and stochastic optical reconstruction microscopy (STORM) to observe that the actin rings are likely to be in the form of twisted ropes containing two long, intertwined actin filaments connected by a dense mesh of aligned spectrins [44]
Shortening and a decrease in intrinsic excitability in axon-bearing dopaminergic neurons in the glomerular layer of olfactory bulbs [79]. These results suggest that bidirectional activity-dependent remodeling of the axon initial segment (AIS) by various types of sensory inputs plays a role in homeostatic adaptation in vivo
Among the many AIS-localized proteins, as shown in Table 1, we focus on three genes: ANK-3, which encodes human ankyrin-3 protein, SPTAN1, which encodes spectrin alpha chain, non-erythrocytic 1 protein, and SPTBN4, which encodes spectrin beta chain, non-erythrocytic 4 protein
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. To focus on the physiological and pathological excitability-dependent plastic change of the AIS structure, we mainly emphasize the role of the AIS in AP initiation in this review rather than polarity regulation. The AIS of a neuron comprises the proximal 20–60 μm at the interface between the axon and cell body. The internal structure of the AIS is characterized by specific features segregated from the axon hillock and neuronal cell body. Ankyrin-G is inserted into the αII (green)/βIV (orange) spectrin te(Nav/Kv7 channels, NF-186, NrCAM) are anchored by ankyrin-G (red). RingsKv1 appear as twisted ropes possessing two long, intertwined actin filaments the distal channels, ADAM22, Tag, and. Actin rings appear as twisted ropes possessing two long, intertwined actin filaments connectedThe by AIS a dense mesh ofcomprises aligned spectrins.
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