Loss of connexin36 increases retinal cell vulnerability to secondary cell loss

Abstract

Accruing evidence indicates that gap junctions are involved in neuronal survival after brain injury. The present study was aimed at clarifying the contribution of the neuronal gap-junction protein connexin36 (Cx36) to secondary cell loss after injury in the mouse retina. A focal retinal lesion was induced by infrared laser photocoagulation. Remarkably, this model allowed spatial and temporal definition of the lesion with high reproducibility. Moreover, Cx36 is abundantly expressed in the retina and plays an essential role in the visual transmission process. Taking advantage of these features, cell death was assessed using TUNEL assay and light and electron microscopy, and the extent of Cx36 expression was studied by immunohistochemistry, Western blot, in situ hybridization and real-time RT-PCR. Secondary cell loss was most prominent between 24 and 48 h after lesioning. This peak was accompanied by an increase in Cx36 expression. When cultured explanted retinas were subjected to gap-junction blockers a significant increase in the extent of secondary cell loss after laser photocoagulation became evident. Using the same experimental paradigm we compared the incidence of cell death in wild-type and Cx36(-/-) mice. A significant increase in total number of TUNEL-positive cells occurred in the Cx36(-/-) mice compared to controls. From these data we conclude that Cx36 contributes to the survival and resistance against damage of retinal cells and thus constitutes a protective factor after traumatic injury of the retina.

A Central Role of Connexin 43 in Hypoxic Preconditioning

“…However, the impact of Cx expression extends beyond bystander death, because expression of Cx43, Cx36, Cx32, or Cx26 increased cellular injury resistance in a gap junction-independent pathway (Oguro et al, 2001;Lin et al, 2003;Striedinger et al, 2005). The phenotypic transformation that increases the injury threshold of Cx-expressing cells has not been established (Lin et al, 2003;Vetterlein et al, 2006) but may be similar to preconditioning involving efflux of neuroprotective agents through open hemichannels.…”

Gap Junctions Are Required for NMDA Receptor–Dependent Cell Death in Developing Neurons

“…Some reports indicate that blocking gap junctions during development, ischemia, or traumatic brain injury rescues cells from apoptosis or necrosis, suggesting that gap junctions contribute to neural cell death (Cusato et al 2003(Cusato et al , 2006de Pina-Benabou et al 2005;Frantseva et al 2002a,b;Nodin et al 2005;Perez Velazquez et al 2006;Rami et al 2001;Rawanduzy et al 1997;Udawatte and Ripps 2005); others demonstrate that gap junctions are neuroprotective (Blanc et al 1998;Nakase et al 2003;Oguro et al 2001;Ozog et al 2002;Siushansian et al 2001;Striedinger et al 2005). Apparently, gap junctions may contribute to both neurodegeneration and neuroprotection depending on the type of connexins, cells coupled, region of the nervous system, stage of development, type of injury, and other factors.…”

Molecular Diversity of Connexin and Pannexin Genes in the Retina of the ZebrafishDanio rerio

“…The knock out of the Cx57 gene, the murine ortholog of the zebrafish drCx55.5, leads to a reduction of the receptive fields of horizontal cells (HCs) (Shelley et al 2006). In a focal retinal lesion model, Cx36 has been shown to contribute to secondary cell loss after injury (Striedinger et al 2005). Nevertheless, it is debatable whether the mouse is the appropriate animal model to study vision.…”