Re-Expression of a Developmentally Restricted Potassium Channel in Autoimmune Demyelination

Abstract

Mechanisms of lesion repair in multiple sclerosis are incompletely understood. To some degree, remyelination can occur, associated with an increase of proliferating oligodendroglial cells. Recently, the expression of potassium channels has been implicated in the control of oligodendrocyte precursor cell proliferation in vitro. We investigated the expression of Kv1.4 potassium channels in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Confocal microscopy revealed expression of Kv1.4 in AN2-positive oligodendrocyte precursor cells and premyelinating oligodendrocytes in vitro but neither in mature oligodendrocytes nor in the spinal cords of healthy adult mice. After induction of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, Kv1.4 immunoreactivity was detected in or around lesions already during disease onset with a peak early and a subsequent decrease in the late phase of the disease. Kv1.4 expression was confined to 2,3-cyclic nucleotide 3-phosphodiesterase-positive oligodendroglial cells, which were actively proliferating and ensheathed naked axons. After a demyelinating episode, the number of Kv1.4 and 2,3-cyclic nucleotide 3-phosphodiesterase double-positive cells was greatly reduced in ciliary neurotrophic factor knockout mice, a model with impaired lesion repair. In summary, the re-expression of an oligodendroglial potassium channel may have a functional implication on oligodendroglial cell cycle progression, thus influencing tissue repair in experimental autoimmune encephalomyelitis and multiple sclerosis.

K+ channel alterations in the progression of experimental autoimmune encephalomyelitis

“…8A,B). Our results are consistent with the upregulation of Kv1.4 channels observed in damaged white matter in the rat model of spinal cord injury (Edwards et al, 2002) and in demyelinated lesions of mouse spinal cord of MOG-induced EAE (Herrero-Herranz et al, 2007). However, these studies show that the up-regulated Kv1.4 mainly resides in OPCs and oligodendrocytes, different from our results.…”

The epigenetics of autoimmunity

“…However, the 20–30% concordance rate for MS among MZ twins 143,144 emphasises the importance of environmental factors in MS pathogenesis possibly via epigenetic mechanisms 142 . Tissue damage implies the activation of developmental pathways 145,146 but in patients with MS these appear to be unregulated in the presence of repair events 147,148 .…”

Oligodendrocytes

“…During development, K v 1.4 appear to be confined to OPCs and premyelinating oligodendrocytes, but not mature oligodendrocytes, although re-expression of K v 1.4 has been observed in experimental autoimmune encephalomyelitis (EAE), suggesting a role in myelination (Herrero-Herranz et al, 2007). Pharmacological or AMPA receptor-mediated blockade of KD strongly inhibits OPC cell cycle progression and proliferation (Borges et al, 1994;Chittajallu et al, 2002;Gallo et al, 1996;Tiwari-Woodruff et al, 2006).…”