ΔFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease

Highlights

• Spontaneous seizures in APP mice increase ΔFosB in the dentate gyrus

• ΔFosB binds and recruits HDAC to suppress expression of genes such as c-fos

• Blocking ΔFosB signaling restores gene expression and normalizes memory in APP mice

• ΔFosB’s long half-life enables persistent regulation of gene expression

Summary

Alzheimer’s disease (AD) is characterized by cognitive decline and 5- to 10-fold increased seizure incidence. How seizures contribute to cognitive decline in AD or other disorders is unclear. We show that spontaneous seizures increase expression of ΔFosB, a highly stable Fos-family transcription factor, in the hippocampus of an AD mouse model. ΔFosB suppressed expression of the immediate early gene c-Fos, which is critical for plasticity and cognition, by binding its promoter and triggering histone deacetylation. Acute histone deacetylase (HDAC) inhibition or inhibition of ΔFosB activity restored c-Fos induction and improved cognition in AD mice. Administration of seizure-inducing agents to nontransgenic mice also resulted in ΔFosB-mediated suppression of c-Fos, suggesting that this mechanism is not confined to AD mice. These results explain observations that c-Fos expression increases after acute neuronal activity but decreases with chronic activity. Moreover, these results indicate a general mechanism by which seizures contribute to persistent cognitive deficits, even during seizure-free periods.