Astrocyte Networks as Therapeutic Targets in Glaucomatous Neurodegeneration

Abstract

Astrocytes are intimately involved in the response to neurodegenerative stress and have become an attractive target for the development of neuroprotective therapies. However, studies often focus on astrocytes as single-cell units. Astrocytes are densely interconnected by gap junctions that are composed primarily of the protein connexin-43 (Cx43) and can function as a broader network of cells. Such networks contribute to a number of important processes, including metabolite distribution and extracellular ionic buffering, and are likely to play an important role in the progression of neurodegenerative disease. This review will focus on the pro-degenerative and pro-survival influence of astrocyte Cx43 in disease progression, with a focus on the roles of gap junctions and hemichannels in the spread of degenerative stress. Finally, we will highlight the specific evidence for targeting these networks in the treatment of glaucomatous neurodegeneration and other optic neuropathies.

Keywords: astrocyte; connexin-43; gap junction; glaucoma.

Figure 1

Schematic cross section of the rodent optic nerve head demonstrating Cx43 gap junctions and hemichannels. Optic nerve astrocytes (dark green) are arranged in a network that lies perpendicular to the direction of axons (yellow). These cells are interconnected via gap junctions composed of two adjoining hexamers of Cx43 (light green), as shown in the upper image inset. The junctions allow for electrical coupling and the nonselective passage of molecules up to ~1.2 kilodaltons in size from cell to cell. A single hexamer can also be unopposed on the astrocyte membrane, forming a hemichannel (lower inset). These can allow direct communication between the cytoplasmic and extracellular spaces.

Figure 2

A working model of the role of Cx43 in neurologic disease. A pathologic insult to neural tissue (a) causes an increased expression of Cx43 (b). Cx43 connexons are assembled and transported to the cell membrane, increasing the number of unopposed hemichannels (c). This allows for the extracellular release of adenosine triphosphate (ATP), causing increased inflammation and microglial activation. Open Cx43 hemichannels also cause cellular swelling. Increased degradation and post-translational modifications, as well as physical swelling of the cell, cause a decrease in Cx43 gap junctional coupling (d). Consequently, there is less available metabolic support from distant astrocytic glycogen stores. There is also a decreased ability to spread out the effect of local increases in extracellular glutamate and potassium through spatial buffering. However, this may also be protective by limiting the spread of calcium waves and other “death signals” to nearby healthy tissue. Cells on the left represent a generic region of CNS pathology, while healthy brain tissue is on the right. Ax, axon; As, astrocyte; and Cx43, connexin-43.

Figure 3

Mechanisms for targeting Cx43 mediated astrocytic networks. Modulation of Cx43 physiology can occur at multiple levels. Substances may decrease the level of expression of Cx43 (a), limiting the production and assembly of both gap junctions and hemichannels. Others may directly target one of these functional structures. Some seek to decrease hemichannel activity by selectively blocking Cx43 hemichannels (b). Often, agents may directly decrease the degree of gap junctional coupling between adjacent cells (c). Other recent drugs have sought to increase the degree of coupling at Cx43 gap junctions (d). Cx43, connexin-43; GJA1, gene encoding Cx43, gap junction alpha-1.