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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.

Key PointsQuestionIs β-amyloid deposition in the brain associated with sleep dysfunction and cognition in elderly individuals with cognitive disorders?FindingsIn this survey study of 52 participants aged 65 years and older, β-amyloid deposition in the precuneus was associated with the number of nocturnal awakenings, whereas β-amyloid deposition in the brainstem was associated with daytime sleepiness. Nocturnal awakenings, but not daytime sleepiness, were associated with poor cognition, and β-amyloid deposition was indirectly associated with cognitive impairment via nocturnal awakenings.MeaningIn elderly individuals with cognitive disorders, a mechanism that involves disruption of nighttime sleep may underlie the association between β-amyloid deposition and cognitive impairment.

Alzheimer's disease (AD) is associated with cognitive decline as well as seizures. Growing evidence indicates seizures contribute to cognitive deficits early in disease, but how they develop and impact cognition are unclear. To investigate potential mechanisms, we studied a mouse model that overexpresses mutant human amyloid precursor protein (APP) with high levels of Aβ. These mice develop generalized epileptiform activity, including nonconvulsive seizures, consistent with alterations in corticothalamic network activity. APP mice exhibited reduced activity marker expression in the reticular thalamic nucleus (nRT), a key inhibitory regulatory nucleus, and increased activity marker expression in downstream thalamic relay targets that project to cortex and limbic structures. Slice recordings revealed impaired cortical inputs to nRT that may contribute to corticothalamic dysfunction. These results are consistent with our findings of impaired sleep maintenance in APP mice. Finally, the severity of sleep impairments predicted the severity of deficits in Morris water maze, suggesting corticothalamic dysfunction may relate to hippocampal dysfunction, and may be a pathophysiological mechanism underlying multiple behavioral and cognitive alterations in AD.

The activity-induced transcription factor ∆FosB has been implicated in Alzheimer’s disease (AD) as a critical regulator of hippocampal function and cognition downstream of seizures and network hyperexcitability. With its long half-life (> 1 week), ∆FosB is well-poised to modulate hippocampal gene expression over extended periods of time, enabling effects to persist even during seizure-free periods. However, the transcriptional mechanisms by which ∆FosB regulates hippocampal function are poorly understood due to lack of identified hippocampal gene targets. To identify putative ∆FosB gene targets, we employed high-throughput sequencing of genomic DNA bound to ∆FosB after chromatin immunoprecipitation (ChIP-sequencing). We compared ChIP-sequencing results from hippocampi of transgenic mice expressing mutant human amyloid precursor protein (APP) and nontransgenic (NTG) wild-type littermates. Surprisingly, only 52 ∆FosB gene targets were shared between NTG and APP mice; the vast majority of targets were unique to one genotype or the other. We also found a functional shift in the repertoire of ∆FosB gene targets between NTG and APP mice. A large number of targets in NTG mice are involved in neurodevelopment and/or cell morphogenesis, whereas in APP mice there is an enrichment of targets involved in regulation of membrane potential and neuronal excitability. RNA-sequencing and quantitative PCR experiments confirmed that expression of putative ∆FosB gene targets were altered in the hippocampus of APP mice. This study provides key insights into functional domains regulated by ∆FosB in the hippocampus, emphasizing remarkably different programs of gene regulation under physiological and pathological conditions.

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