The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition1,2,3, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures4,5,6,7. 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 through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) 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 the DG of individuals 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 through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures.
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We thank R. Jagirdar for helpful comments on the manuscript. This work was supported by the Margaret Q. Landenberger Research Foundation (J.C.), the Hassel Family Foundation (J.C.), National Institutes of Health grant NS085171 (J.C.), F30-AG048710 (J.C.Y.), AG051848, BX003040, AG0051839, and AG005131 (R.A.R.), and the New York State Office of Mental Health (H.E.S., J.J.F.).
The authors declare no competing financial interests.
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You, J., Muralidharan, K., Park, J. et al. Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits. Nat Med 23, 1377–1383 (2017). https://doi.org/10.1038/nm.4413
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