Remodeling of the Axon Initial Segment After Focal Cortical and White Matter Stroke

Abstract

Background and Purpose— Recovery from stroke requires neuroplasticity within surviving adjacent cortex. The axon initial segment (AIS) is the site of action potential initiation and a focal point for tuning of neuronal excitability. Remodeling of the AIS may be important to neuroplasticity after stroke. Methods— Focal cortical stroke in forelimb motor cortex was induced by photothrombosis and compared with sham controls. White matter stroke was produced through stereotactic injection of a vasoconstrictor together with biotinylated dextran amine to retrogradely label injured cortical neurons. AIS length, morphology and number were measured using immunofluorescence and confocal microscopy 2 weeks after stroke. Results— Within the peri-infarct cortex and after white matter stroke, AIS length decreases. This shortening is accompanied by altered AIS morphology. In peri-infarct cortex, the decrease in AIS length after stroke occurs from the distal end of the AIS, resulting in a Nav1.6. γ-aminobutyric acid type A receptor-α2 subunit staining at axoaxonic synapses along the AIS is significantly decreased. In addition, a significant increase in small, immature initial segments is present in layers 2/3 of peri-infarct cortex, reflecting maturation of axonal sprouting and new initial segments from surviving neurons. Conclusions— Stroke alters the compartmental morphology of surviving adjacent neurons in peri-infarct cortex and in neurons whose distal axons are injured by white matter stroke. With a key role in modulation of neuronal excitability, these changes at the AIS may contribute to altered neuronal excitability after injury and prove crucial to increasing neuroplasticity in surviving tissue affected by stroke.