Synaptic Activity Couples Inducible Transcription to Genome Preservation in the Mammalian Brain

Abstract

Neuronal activity is critical for adaptive circuit remodeling but poses an inherent risk to the stability of the genome across the long lifespan of post-mitotic neurons. In addition to the potential genomic damage from reactive metabolic byproducts generated during periods of heightened neuronal activity, the rapid activity-induced changes in gene expression that follow neuronal stimulation are known to generate recurrent DNA double-strand breaks (DSBs) at critical genomic regulatory elements such as the promoters of inducible genes. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened synaptic activity is not known. Here we identify a neuronal-specific DNA repair mechanism embedded within the neuronal response to stimulation via a new form of the NuA4 chromatin modifying complex that assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex from the brain and demonstrate its functions in eliciting activity-dependent changes to neuronal transcriptomes and circuitry. By characterizing the landscape of activity-induced DNA double-strand breaks in the brain, we show that NPAS4-NuA4 binds to recurrently damaged regulatory elements and recruits additional DNA repair machinery to stimulate their repair. Gene regulatory elements bound by NPAS4-NuA4 are partially protected from age-dependent accumulation of somatic mutations. Impaired NPAS4-NuA4 signaling leads to a cascade of cellular defects including dysregulated activity-dependent transcriptional responses, loss of control over neuronal inhibition, and genome instability, ultimately culminating in reduced organismal lifespan. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental disorders and autism. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation and whose disruption may contribute to developmental disorders, neurodegeneration, and aging.