Connexin 43/47 channels are important for astrocyte/ oligodendrocyte cross-talk in myelination and demyelination

Abstract

The gap junctions (GJs), which form intercellular communicating channels between two apposing cells or form hemichannel with extracellular environment, perform crucial functions to maintain small molecule homeostasis. The central nervous system (CNS) GJs are important for maintenance of myelin sheath and neuronal activity. Connexin (Cx) proteins are building blocks of GJs. Recent cell-biological investigations show that amongst the CNS specific Cxs, the most abundant Cx protein, Cx43 and its oligodendrocytic coupling partner Cx47 primarily important for maintenance of CNS myelin. Recent investigations elucidate that the expression of Cx43 and Cx47 is very important to maintain K? buffering and nutrient homeostasis in oligodendrocytes, CNS myelin and oligodendrocyte function. The investigations on Multiple Sclerosis (MS) patient samples and EAE hypothesized that the functional loss of Cx43/Cx47 could be associated with spread of chronic MS lesions. Exploring the mechanism of initial GJ alteration and its effect on demyelination in this model of MS might play a primary role to understand the basis of altered CNS homeostasis, observed during MS. In this review, we mainly discuss the role of CNS GJs, specifically the Cx43/Cx47 axis in the perspective of demyelination.

Figure 1

MHV infection as a model of gliopathy and demyelination. The demyelinating stains of MHVs cause meningitis (A) and encephalitis (B, C). The chronic infection in CNS is majorly restricted to brain and causes demyelination (D) and axonal loss (E). During acute phase, brain astrocytes are infected as demonstrated by colocalization of GFAP and viral-N staining (F).

Figure 2

Neurotropic demyelinating strain of mouse hepatitis virus (MHV-A59) infection leads to downregulation and intracellular retention of Connexin43 in neonatal mouse brain derived primary astrocytes. The illustration is an amalgamation of immunofluorescence images of primary astrocytes, stained with either MHV-A59 nucleocapsid (N; green) and Connexin43 (Cx43; red in large central panel and top left inset) or GFAP (green) and Cx43 (red in bottom right inset). Nuclei were counterstained with DAPI (blue). The large central panel is MHV-A59 infected primary astrocytes where Cx43 was retained in the intracellular compartment, specifically in the virus infected cells. In the same culture, the cells which were not infected by MHV-A59, Cx43 was present as prominent puncta at the surface of two adjacent cells. The image is modified using Adobe Photoshop for a better understanding of Cx43 localization in uninfected and infected cells. The top left inset is a magnified infected single astrocyte where intracellular compartment retained Cx43 mostly colocalized with anti-N staining in a perinuclear compartment. The bottom right inset is a magnified uninfected single mock infected cell where discrete Cx43 puncta were present at the cell surface of GFAP positive astrocyte.

Figure 3

Cell-to-cell communication and gliopathy in MHV induced demyelination. Demyelinating stain of MHV can infect astrocytes both in vivo and in vitro. This infection causes depletion of Cx43 expression and also restricts Cx43 protein trafficking to cell surface by a MT-dependent mechanism during acute phase of inflammation. The loss of Cx43 induces persistent loss of Cx47, which is associated with loss of myelin proteins.