Oxidative Stress Induces Disruption of the Axon Initial Segment

ASN Neuro. 2017 Nov-Dec;9(6):1759091417745426. doi: 10.1177/1759091417745426.


The axon initial segment (AIS), the domain responsible for action potential initiation and maintenance of neuronal polarity, is targeted for disruption in a variety of central nervous system pathological insults. Previous work in our laboratory implicates oxidative stress as a potential mediator of structural AIS alterations in two separate mouse models of central nervous system inflammation, as these effects were attenuated following reactive oxygen species scavenging and NADPH oxidase-2 ablation. While these studies suggest a role for oxidative stress in modulation of the AIS, the direct effects of reactive oxygen and nitrogen species (ROS/RNS) on the stability of this domain remain unclear. Here, we demonstrate that oxidative stress, as induced through treatment with 3-morpholinosydnonimine (SIN-1), a spontaneous ROS/RNS generator, drives a reversible loss of AIS protein clustering in primary cortical neurons in vitro. Pharmacological inhibition of both voltage-dependent and intracellular calcium (Ca2+) channels suggests that this mechanism of AIS disruption involves Ca2+ entry specifically through L-type voltage-dependent Ca2+ channels and its release from IP3-gated intracellular stores. Furthermore, ROS/RNS-induced AIS disruption is dependent upon activation of calpain, a Ca2+-activated protease previously shown to drive AIS modulation. Overall, we demonstrate for the first time that oxidative stress, as induced through exogenously applied ROS/RNS, is capable of driving structural alterations in the AIS complex.

Keywords: axon initial segment; calcium; calpain; oxidative stress; reactive nitrogen species; reactive oxygen species.

MeSH terms

  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / pharmacology
  • Animals
  • Axon Initial Segment / drug effects
  • Axon Initial Segment / physiology*
  • Calcium Channel Agonists / pharmacology
  • Calcium Channel Blockers / pharmacology
  • Cell Survival / drug effects
  • Cerebral Cortex / cytology
  • Dizocilpine Maleate / pharmacology
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology
  • Female
  • Immunosuppressive Agents / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Molsidomine / analogs & derivatives
  • Molsidomine / pharmacology
  • NADPH Oxidase 2 / metabolism
  • Neurons / cytology*
  • Neuroprotective Agents / pharmacology
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Pregnancy
  • Reactive Oxygen Species / metabolism
  • Tacrolimus / pharmacology


  • Calcium Channel Agonists
  • Calcium Channel Blockers
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • linsidomine
  • Dizocilpine Maleate
  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
  • Molsidomine
  • NADPH Oxidase 2
  • Tacrolimus