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

Cell Reports

Lijuan Zhao¹  Iraklis Petrof¹  Daniel M. Iascone¹  Jason C. You¹  Xiaohong Zhang¹  Brian F. Corbett¹  Chia-Hsuan Fu¹  Annie A. Ashok¹  Suzan Aschmies¹  Umberto Tosi¹  Anupam Hazra¹  Mark S. Pyfer¹  Jeannie Chin¹  Gabriel S. Stephens²  Eric J. Nestler³ 

[1] 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;Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;

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

DOI  :  10.1016/j.celrep.2017.06.040

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown