Dysfunction of oligodendrocyte inwardly rectifying potassium channel in a rat model of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting lower and upper motor neurons, leading to muscle atrophy, paralysis and death. Although ALS is characterized by motoneuron degeneration, non-neuronal cells such as oligodendrocytes play an essential role in disease onset and progression. The aim of this study was to investigate functional properties of oligodendrocytes in the ALS with particular focus on their role in the regulation of extracellular K+ through inwardly rectifying potassium channel Kir4.1 abundantly expressed in these glial cells. We employed immunolabeling of Kir4.1, and oligodendrocyte-specific marker CNPase, to examine the expression of Kir4.1 in oligodendrocytes of the lumbar spinal cord of SOD1G93A rat model of ALS. Furthermore, whole-cell patch-clamp recordings were performed on primary oligodendrocyte cultures from ALS and control rats to investigate functional properties of these cells. Our data show reduced expression of Kir4.1 in the oligodendrocytes in the lumbar spinal cord of SOD1G93A rat compared to control. Moreover, we found elevated number of dysmorphic oligodendrocytes in the ALS spinal cord, indicative of a degenerative phenotype. Oligodendrocytes isolated from SOD1G93A spinal cord display similar processes ramification as the control, however expressing a lower level of Kir4.1. Electrophysiological examination of cultured SOD1G93A oligodendrocytes revealed compromised membrane properties and diminished inward currents in comparison to control. In addition, the Ba2+-sensitive Kir current is decreased in ALS oligodendrocytes. Altogether, our findings provide the evidence of impaired Kir4.1 expression and function in SOD1G93A spinal cord oligodendrocytes suggesting a critical role of oligodendrocyte Kir4.1 channel in ALS pathophysiology.