Short- and long-term plasticity at the axon initial segment

Abstract

The axon initial segment (AIS) is a highly specialized neuronal subregion that is the site of action potential initiation and the boundary between axonal and somatodendritic compartments. In recent years, our understanding of the molecular structure of the AIS, its maturation, and its multiple fundamental roles in neuronal function has seen major advances. We are beginning to appreciate that the AIS is dynamically regulated, both over short timescales via adaptations in ion channel function, and long timescales via activity-dependent structural reorganization. Here, we review results from this emerging field highlighting how structural and functional plasticity relate to the development of the initial segment, and to neuronal disorders linked to AIS dysfunction.

Figure 1.

Molecular composition of the AIS. A, Na⁺ channel immunohistochemistry in neocortex reveals differential distribution of Na_V1.2 and 1.6 isoforms to the proximal and distal AIS, respectively. Dashes outline somata. Image is a maximum-intensity projection of a 5-μm-thick confocal stack. Scale bar is 10 μm in A–C. B, Cultured rat hippocampal neuron triple labeled for MAP2, acetylated tubulin, and ankG to label the axon initial segment. C, Cultured hippocampal neuron expressing GFP, stained for the AIS-localized cell adhesion molecule neurofascin (NF)-186. Asterisk, NF-186 labeling of neighboring, non-GFP-positive neuron. D, A simplified, non-comprehensive diagram of some of the molecules found at the AIS. See text for abbreviations.

Figure 2.

Function and modulation of AIS ion channels. A, Schematic detailing roles of Na⁺ channel subtypes in AP initiation and backpropagation in neocortical pyramidal neurons. Accumulation of the low-threshold Na_V1.6 channels at the distal AIS determines the lowest threshold for AP initiation, whereas accumulation of the high-threshold Na_V1.2 channels at the proximal AIS promotes AP backpropagation to the soma and dendrites. B, Axonal K_V1 channels can shape the waveforms of axonal APs. Spreading of the somatic subthreshold depolarizations into the axon (top) may inactivate some axonal K_V1 channels (middle), increasing axonal AP duration (bottom). This in turn enhances neurotransmitter release. C, AIS low-voltage activated Ca²⁺ channels (Ca_V3) promote AP bursts in auditory brainstem interneurons. Their downregulation via local dopaminergic signaling suppresses spike output in response to somatic depolarization. DA, Dopamine.

Figure 3.

Long-term AIS plasticity. In chick NM, auditory deprivation leads to an increase in AIS length and increased neuronal excitability. In rat hippocampal neurons (HPC), chronic depolarization leads to a distal shift in AIS location and decreased neuronal excitability, although the AIS can return to its original position after recovery in control conditions.