Abnormal axonal physiology is associated with altered expression and distribution of Kv1.1 and Kv1.2 K+ channels after chronic spinal cord injury

Dysfunction of surviving axons which traverse the site of spinal cord injur y (SCI) has been linked to altered sensitivity to the K+ channel blocker 4- aminopyridine (4-AP) and appears to contribute to post-traumatic neurologic al deficits although the underlying mechanisms remain unclear. In this stud y, sucrose gap electrophysiology in isolated dorsal column strips, Western blotting and confocal immunofluorescence microscopy were used to identify t he K+ channels associated with axonal dysfunction after chronic (6-8 weeks postinjury) clip compresssion SCI of the thoracic cord at T7 in rats. The K + channel blockers 4-AP (200 mu m, 1 mm and 10 mm) and alpha-dendrotoxin (a lpha-DTX, 500 nm) resulted in a significant relative increase in the amplit ude and area of compound action potentials (CAP) recorded from chronically injured dorsal column axons in comparison with control noninjured preparati ons. In contrast, TEA (10 mm) and CsCl (2 mm) had similar effects on injure d and control spinal cord axons. Western blotting and quantitative immunofl uorescence microscopy showed increased expression of Kv1.1 and Kv1.2 K+ cha nnel proteins on spinal cord axons following injury. In addition, Kv1.1 and Kv1.2 showed a dispersed staining pattern along injured axons in contrast to a paired juxtaparanodal localization in uninjured spinal cord axons. Fur thermore, labelled alpha-DTX colocalized with Kv1.1 and Kv1.2 along axons. These findings suggest a novel mechanism of axonal dysfunction after SCI wh ereby an increased 4-AP- and alpha-DTX-sensitive K+ conductance, mediated i n part by increased Kv1.1 and Kv1.2 K+ channel expression, contributes to a bnormal axonal physiology in surviving axons.