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

被引：77

作者：

Corbett, Brian F. ^{[1
,2
]}

You, Jason C. ^{[1
,2
]}

Zhang, Xiaohong ^{[1
,2
]}

Pyfer, Mark S. ^{[1
,2
]}

Tosi, Umberto ^{[1
,2
]}

Iascone, Daniel M. ^{[1
,2
]}

Petrof, Iraklis ^{[1
,2
]}

Hazra, Anupam ^{[1
,2
]}

Fu, Chia-Hsuan ^{[1
,2
,5
]}

Stephens, Gabriel S. ^{[5
]}

Ashok, Annie A. ^{[1
,2
]}

Aschmies, Suzan ^{[1
,2
]}

Zhao, Lijuan ^{[1
,2
]}

Nestler, Eric J. ^{[3
,4
]}

Chin, Jeannie ^{[1
,2
,5
]}

机构：

[1] Thomas Jefferson Univ, Dept Neurosci, Philadelphia, PA 19107 USA

[2] Thomas Jefferson Univ, Farber Inst Neurosci, Philadelphia, PA 19107 USA

[3] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA

[5] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA

来源：

CELL REPORTS | 2017年 / 20卷 / 02期

关键词：

IMMEDIATE-EARLY GENES; AMYLOID-PRECURSOR-PROTEIN; LONG-TERM-MEMORY; C-FOS; EPILEPTIFORM ACTIVITY; HISTONE ACETYLATION; SYNAPTIC PLASTICITY; NEURONAL-ACTIVITY; MOLECULAR SWITCH; RAT HIPPOCAMPUS;

D O I：

10.1016/j.celrep.2017.06.040

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Alzheimer's disease (AD) is characterized by cognitive decline and 5-to10- 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 Delta FosB, a highly stable Fos-family transcription factor, in the hippocampus of an AD mouse model. DFosB 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 DFosB activity restored c-Fos induction and improved cognition in AD mice. Administration of seizure-inducing agents to nontransgenic mice also resulted in Delta FosB-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.

引用

页码：344 / 355

页数：12

共 70 条

[1] Incidence and predictors of seizures in patients with Alzheimer's disease [J].