CREB binding and activity in brain: regional specificity and induction by electroconvulsive seizure

The transcription factor cyclic adenosine monophosphate response element binding protein (CREB) orchestrates diverse neurobiological processes including cell differentiation, survival, and plasticity. Alterations in CREB-mediated transcription have been implicated in numerous central nervous system (CNS) disorders including depression, anxiety, addiction, and cognitive decline. However, it remains unclear how CREB contributes to normal and aberrant CNS function, as the identity of CREB-regulated genes in brain and the regional and temporal dynamics of CREB function remain largely undetermined.

We combined microarray and chromatin immunoprecipitation technology to analyze CREB-DNA interactions in brain. We compared the occupancy and activity of CREB at gene promoters in rat frontal cortex, hippocampus, and striatum before and after a rodent model of electroconvulsive therapy.

Our analysis identified >860 CREB binding sites in rat brain. We identified multiple genomic loci enriched with CREB binding sites and find that CREB-occupied transcripts interact extensively to promote cell proliferation, plasticity, and resiliency. We discovered regional differences in CREB occupancy and activity that explain, in part, the diverse biological and behavioral outputs of CREB activity in frontal cortex, hippocampus, and striatum. Electroconvulsive seizure rapidly increased CREB occupancy and/or phosphorylation at select promoters, demonstrating that both events contribute to the temporal regulation of the CREB transcriptome.

Our data provide a mechanistic basis for CREB's ability to integrate regional and temporal cues to orchestrate state-specific patterns of transcription in the brain, indicate that CREB is an important mediator of the biological responses to electroconvulsive seizure, and provide global mechanistic insights into CREB's role in psychiatric and cognitive function.