The Connexin43 C-Terminal Region Mediates Neuroprotection During Stroke

Connexin43 plays an important role in neuroprotection in experimental stroke models; reducing the expression of this gap junction protein in astrocytes enhances injury upon middle cerebral artery Occlusion (MCAO). Because the C-terminal region of connexin43 is important for channel activity, we carried out MCAO stroke experiments in mice expressing a truncated form of connexin43 (Cx43 Delta CT mice). Brain sections were analyzed for infarct volume, astrogliosis, and inflammatory cell invasion 4 days after MCAO. Adult cortices and astrocyte cultures were examined for connexin43 (Cx43) expression by immunohistochemistry and Western blot. Cultured astrocytes were also examined for dye Coupling, channel conductance, hemichannel activity, and Ca2+ wave propagation. The Cx43 Delta CT mice exhibit enhanced cerebral injury after stroke. Astrogliosis was reduced and inflammatory cell invasion was increased in the peri-infarct region in these mice compared with controls; Cx43 expression was also altered. Lastly, cultured astrocytes from Cx43 Delta CT mice were less coupled and displayed alterations in channel gating, hemichannel activity, and Ca2+ wave properties. These results Suggest that astrocytic Cx43 contributed to the regulation of cell death after stroke and support the view that the Cx43 C-terminal region is important in protection in cerebral ischemia.