Oligodendrocyte Gap Junction Loss and Disconnection From Reactive Astrocytes in Multiple Sclerosis Gray Matter

Abstract

Gap junctions are essential for glial cell function and have been increasingly implicated in multiple sclerosis (MS). Because increasing cortical abnormalities correlate with disease progression and cognitive dysfunction, we examined the expression of oligodendrocytic connexin32 (Cx32) and Cx47 and their astrocytic partners Cx30 and Cx43 in cortical lesions and normal-appearing gray matter (NAGM) in MS patients. Postmortem brain tissue samples from 9 MS cases were compared with 10 controls using real-time polymerase chain reaction, immunoblot, and immunohistochemical analyses. Connexin32 and Cx47 gap junction formation in oligodendrocytes was reduced within lesions, whereas Cx32 loss also extended to NAGM. In contrast, astrocytic Cx30 expression was increased within cortical lesions, whereas Cx43 was elevated in both lesions and NAGM. Diffuse microglial activation and marked astrogliotic changes accompanied these connexin abnormalities. Increased expression of Cx43 correlated with inflammatory load (r = 0.828, p = 0.042), whereas Cx32 expression correlated with longer disease duration and, therefore, milder course (r = 0.825, p = 0.043). Thus, there is a loss of intramyelin and intercellular oligodendrocyte gap junctions in MS gray matter lesions and NAGM, whereas interastrocytic gap junctions are increased, reflecting astrogliosis. These changes correlate with inflammation and disease duration and suggest that disconnection of oligodendrocytes from reactive astrocytes may play a role in failed remyelination and disease progression.

Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling

“…This suggests that EAAT2 expression might be reduced in individual astrocyte as observed for CX43. Taken together, our analysis demonstrates that CX43, the major gap junction protein expressed by astrocytes and involved in the formation of the astrocyte syncytium, is downregulated in MS NAGM most prominently in layers III-V. A recent study identified a higher CX43 expression in MS cortical NAGM in comparison to control samples (Markoullis et al, 2014). Whether this discrepancy is due to the smaller sample number investigated or to the heterogeneous expression of CX43, which we also observed in control cases, cannot be verified.…”

Increased Cx32 expression in spinal cord TrkB oligodendrocytes following peripheral axon injury

“…To our knowledge, we are the first to show that peripheral axon injury can lead to an increase in Cx32 protein expression in the central nervous system and that, in the spinal cord, OL progenitor cells express Cx32. Similar to previous reports [8, 15] we observed Cx32 expression in both GM and WM subregions of the spinal cord with Cx32 expression was found in the processes and cell bodies of OPCs and on the perimeter of mature OLs [21,22] expressing CC1 or TrkB.…”

“…These glial cell changes appear to contribute to neuronal survival and regeneration [4,6], yet the specific roles served by the activation of astrocytes, microglia as well as oligodendrocytes (OLs) following peripheral axon injury are poorly understood. In particular, the plasticity of cells in the OL lineage is not well studied, yet the dysregulation of OLs contributes to demyelinating disorders [7,8], mood disorders [9], and lack of recovery following both traumatic brain injury and spinal cord injury [10,11]. Therefore a better understanding of the many factors that influence these cells has important clinical implications.…”

Connexins and pannexins: At the junction of neuro‐glial homeostasis & disease

“…Seizure activity could also arise as a result of loss of oligodendrocyte Cxs and reduction of Cx43 expression as observed in immune‐mediated mouse models of MS (Brand‐Schieber et al, ; Markoullis et al, ). Furthermore, demyelinating MS lesions show evidence of GJ dysregulation, where inflamed white matter tracts and adjacent normal appearing tissue exhibit decreased Cx43 expression and oligodendrocyte uncoupling from reactive astrocytes (Markoullis et al, ; Markoullis et al, ). In addition, MS patients are three to six times more likely to develop epilepsy than the overall population (Poser & Brinar, ).…”