Connexin43 following partial optic nerve transection

Abstract

Retinal ganglion cell (RGC) loss is the common pathway of optic nerve injury, a leading cause of blindness worldwide. This thesis investigates the relationship between glial connexin43 (Cx43), the most ubiquitously expressed gap junction protein in the central nervous system, and RGC loss in an in vivo model of optic nerve injury. Partial, unilateral superior optic nerve transection was performed in Wistar rats. Optic nerves and retinas were evaluated at various timepoints up to 56 days after injury. In the optic nerve, an increase in Cx43 was observed around the transection site as early as 4 hours after injury that was still evident by 8 and 24 hours. At 3 and 7 days, a decrease in Cx43 was observed at the cut edges of the injury site, progressing to decreased Cx43 levels at the lesion centre at 14, 28 and 56 days. In the optic nerve head, a transient increase in Cx43 occurred in the lamina region at 3 and 7 days post-injury. In the retina, superior Cx43 peaked at 3 days (192.1% of control; P = 0.0002) and 28 days (212.1% of control P < 0.0001), and troughed at 14 days (73.8% of control; P = 0.0028) and 56 days (72.5% of control; P = 0.0232) after injury. Inferior Cx43 was elevated at only 28 days (127.4% of control; P = 0.0481) after injury. Superior RGC loss began at 3 days (84.0% of control; P = 0.0454) and continued to decline by 56 days (18.8% of control; P < 0.0001). Inferior RGC loss began at 28 days (73.4% of control; P = 0.0021). The initial increase in superior retinal Cx43 preceded significant superior RGC loss, with superior RGC counts 66.9% of controls at 7 days following injury. By comparison, inferior retinal Cx43 only significantly changed at 28 days post-injury, paralleled by significant inferior RGC loss at 28 days. The timing of the Cx43 changes suggests that RGC and glial interplay has a highly significant role in the regulation of RGC death following injury. The data provided in this thesis supports the participation of astrocytic upregulation of Cx43 in the early phenomena of the injury process. Retinal astrocytes may well be reacting to local signals and events generated by RGC body injury. Further studies should be directed at the modulation of Cx43 to determine its definitive impact on RGC survival.