The axon initial segment in nervous system disease and injury

Abstract

The axon initial segment (AIS), with its dense clusters of voltage-gated ion channels decorating the axonal membrane, regulates action potential initiation and modulation. The AIS also functions as a barrier to maintain axodendritic polarity, and its precise axonal location contributes to the fine-tuning of neuronal excitability. Therefore, it is not surprising that mutations in AIS-related genes, disruption of the molecular organization of the AIS and altered AIS ion channel expression, function, location and/or density are emerging as key players in neurological disorders. Here, we consider the role of the AIS in nervous system disease and injury.

Fig. 1

The AIS is decorated by dense clusters of voltage-gated Na⁺ channels and is selectively innervated by GABAergic interneurons. (A) Voltage-gated Na⁺ channel Na_v1.6 (red) is highly enriched at the AIS of cerebellar Purkinje neurons. Purkinje cell marker calbindin (green) is restricted to the somatodendritic domain. (B) AIS proteins βIV spectrin (green) and Nfasc186 (red) assemble within the proximal axon of a cultured hippocampal neuron independently of glial interaction or extrinsic factors. (C) Glutamic acid decarboxylase (GAD-67)-positive chandelier cell axonal cartridges (red) contact the distal AIS, denoted by βIV spectrin (green), in mouse neocortex. Scale bars: 20 μm.

Fig. 2

AIS protein association with nervous system pathologies and injuries. Ion channels, CAMs, neurotransmitter receptors and cytoskeletal adaptor proteins enriched at the AIS have been linked to neurological disorders including epilepsy, neuropsychiatric developmental disorders and autoimmune disorders. Nervous system injury can also cause disassembly of the AIS. ECM, extracellular matrix.