Targeted activation of CREB in reactive astrocytes is neuroprotective in focal acute cortical injury

The clinical challenge in acute injury as in traumatic brain injury (TBI) is to halt the delayed neuronal loss that occurs hours and days after the insult. Here we report that the activation of CREB‐dependent transcription in reactive astrocytes prevents secondary injury in cerebral cortex after experimental TBI. The study was performed in a novel bitransgenic mouse in which a constitutively active CREB, VP16‐CREB, was targeted to astrocytes with the Tet‐Off system. Using histochemistry, qPCR, and gene profiling we found less neuronal death and damage, reduced macrophage infiltration, preserved mitochondria, and rescued expression of genes related to mitochondrial metabolism in bitransgenic mice as compared to wild type littermates. Finally, with meta‐analyses using publicly available databases we identified a core set of VP16‐CREB candidate target genes that may account for the neuroprotective effect. Enhancing CREB activity in astrocytes thus emerges as a novel avenue in acute brain post‐injury therapeutics. GLIA 2016;64:853–874 Main Points Protection against brain injury by the transgenetic activation of CREB in astrocytes. Protection is effective even when intervening after the insult. Protection is associated with preserved mitochondria and reduced inflammation.