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Τρίτη 11 Ιουλίου 2017

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

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Brian F. Corbett, Jason C. You, Xiaohong Zhang, Mark S. Pyfer, Umberto Tosi, Daniel M. Iascone, Iraklis Petrof, Anupam Hazra, Chia-Hsuan Fu, Gabriel S. Stephens, Annie A. Ashok, Suzan Aschmies, Lijuan Zhao, Eric J. Nestler, Jeannie Chin
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.

Graphical abstract

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Teaser

Corbett et al. report that, in mouse models of Alzheimer's disease, spontaneous seizures induce expression of ΔFosB in the dentate gyrus, where it triggers histone modifications and suppresses gene expression important for memory. Due to its long half-life, ΔFosB may persistently affect gene expression and memory, even when seizures are infrequent.


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