The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition1-3, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures4-7. In Alzheimer's disease (AD) and epilepsy, both of which are accompanied by recurrent seizures8, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG)4,9,10. However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism by which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus of mouse models of AD and seizures, where it binds and triggers histone deacetylation at the calbindin gene (Calb1) promoter, and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of ΔFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of ΔFosB and calbindin expression are inversely related in DG of patients with temporal lobe epilepsy (TLE) or AD, and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by ΔFosB is one mechanism by which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures.

Summary Alzheimer's disease (AD) is characterized by cognitive decline and 5–10 fold increased seizure incidence. How seizures contribute to cognitive decline in AD or other disorders is unclear. We show 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 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 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.

BACE1 is the rate-limiting enzyme that cleaves amyloid precursor protein (APP) to produce the amyloid ␤ peptides that accumulate in Alzheimer's disease (AD). BACE1, which is elevated in AD patients and APP transgenic mice, also cleaves the ␤2-subunit of voltage-gated sodium channels (Nav␤2). Although increased BACE1 levels are associated with Nav␤2 cleavage in AD patients, whether Nav␤2 cleavage occurs in APP mice had not yet been examined. Such a finding would be of interest because of its potential impact on neuronal activity: previous studies demonstrated that BACE1-overexpressing mice exhibit excessive cleavage of Nav␤2 and reduced sodium current density, but the phenotype associated with loss of function mutations in either Nav␤-subunits or pore-forming ␣-subunits is epilepsy. Because mounting evidence suggests that epileptiform activity may play an important role in the development of AD-related cognitive deficits, we examined whether enhanced cleavage of Nav␤2 occurs in APP transgenic mice, and whether it is associated with aberrant neuronal activity and cognitive deficits. We found increased levels of BACE1 expression and Nav␤2 cleavage fragments in cortical lysates from APP transgenic mice, as well as associated alterations in Nav1.1␣ expression and localization. Both pyramidal neurons and inhibitory interneurons exhibited evidence of increased Nav␤2 cleavage. Moreover, the magnitude of alterations in sodium channel subunits was associated with aberrant EEG activity and impairments in the Morris water maze. Together, these results suggest that altered processing of voltage-gated sodium channels may contribute to aberrant neuronal activity and cognitive deficits in AD.