Increased apoptosis and inflammation after focal brain ischemia in mice lacking connexin43 in astrocytes.
Astrocytes secrete cytokines and neurotrophic factors to neurons, consistent with a neurosupportive role for astrocytes. However, in ischemic or metabolic insults, the function of astrocytic gap junctions composed mainly from connexin43 (Cx43) remains controversial. We have previously shown that heterozygous Cx43 null mice subjected to middle cerebral artery occlusion exhibited significantly enhanced stroke volume and apoptosis compared to wild-type mice. In this study, we used mice in which the human GFAP promoter-driven cre transgene deletes the floxed Cx43 gene in astrocytes, excluding the effects from reduced Cx43 expression in many other cell types as well as astrocytes. We induced focal brain ischemia in mice lacking Cx43 in astrocytes [Cre(+)] and control littermates [Cre(-)]. Cre(+) mice showed a significantly increased stroke volume and enhanced apoptosis, detected by terminal dUTP nick-end labeling and caspase-3 immunostaining, compared to Cre(-) mice. Inflammatory response assessed by the microglial marker CD11b was amplified in the penumbra of Cre(+) mice compared to that of Cre(-) mice. Our results suggest that astrocytic gap junctions could be important for the regulation of neuronal apoptosis and the inflammatory response after stroke. These findings support the view that astrocytes play a critical role in neuroprotection during ischemic insults.
Nakase
Taizen
T
Department of Anatomy and Cell Biology, the University of British Columbia, Vancouver, British Columbia.
Söhl
Goran
G
Theis
Martin
M
Willecke
Klaus
K
Naus
Christian C G
CC
D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000166:cytology / Q000473:pathology* / Q000502:physiology; D002545:Brain Ischemia / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D018031:Connexin 43 / Q000172:deficiency* / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012016:Reference Values; D013318:Stroke Volume
D018031:Connexin 43; D005904:Glial Fibrillary Acidic Protein