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Cell Rep. 2017 Jul 11;20(2):344-355. doi: 10.1016/j.celrep.2017.06.040.

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

Author information

1
Department of Neuroscience and Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA.
2
Department of Neuroscience and Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
4
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Department of Neuroscience and Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: jeannie.chin@bcm.edu.

Abstract

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.

KEYWORDS:

Fos; acetylation; activity; amyloid; dentate gyrus; epigenetic; epilepsy; hippocampus; memory; seizures

PMID:
28700937
PMCID:
PMC5785235
DOI:
10.1016/j.celrep.2017.06.040
[Indexed for MEDLINE]
Free PMC Article

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