Histone Modification of Nedd4 Ubiquitin Ligase Controls the Loss of AMPA Receptors and Cognitive Impairment Induced by Repeated Stress

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Jing WeiZhen Yan

Abstract

Stress and the major stress hormone corticosterone induce profound influences in the brain. Altered histone modification and transcriptional dysfunction have been implicated in stress-related mental disorders. We previously found that repeated stress caused an impairment of prefrontal cortex (PFC)-mediated cognitive functions by increasing the ubiquitination and degradation of AMPA-type glutamate receptors via a mechanism depending on the E3 ubiquitin ligase Nedd4. Here, we demonstrated that in PFC of repeatedly stressed rats, active glucocorticoid receptor had the increased binding to the glucocorticoid response element of histone deacetylase 2 (HDAC2) promoter, resulting in the upregulation of HDAC2. Inhibition or knock-down of HDAC2 blocked the stress-induced impairment of synaptic transmission, AMPAR expression, and recognition memory. Furthermore, we found that, in stressed animals, the HDAC2-dependent downregulation of histone methyltransferase Ehmt2 (G9a) led to the loss of repressive histone methylation at the Nedd4-1 promoter and the transcriptional activation of Nedd4. These results have provided an epigenetic mechanism and a potential treatment strategy for the detrimental effects of chronic stress. Prolonged stress ...Continue Reading

Citations

Feb 9, 2017·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Jia ChengZhen Yan
Aug 31, 2017·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Yu-Cheng HoHsien-Yu Peng
Jan 23, 2019·Brain : a Journal of Neurology·Yan ZhengZhen Yan
Jul 28, 2016·Molecular Psychiatry·J-S SeoP Greengard
Sep 4, 2019·Translational Psychiatry·A StarnawskaL Christiansen
May 16, 2018·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Kaijie MaZhen Yan
Oct 11, 2017·The International Journal of Neuropsychopharmacology·Eunice Y YuenZhen Yan
Mar 23, 2018·Acta Pharmacologica Sinica·Meng-Yi Xu, Albert H C Wong
Jan 31, 2019·Nature Reviews. Neuroscience·Rianne R Campbell, Marcelo A Wood
Mar 7, 2019·Archives of Pharmacal Research·Heesung Sohn, Mikyoung Park
Feb 28, 2021·Cellular and Molecular Neurobiology·Xu ZhouLili Cui
Dec 12, 2021·Nature Reviews. Neuroscience·Gerard SanacoraMaurizio Popoli

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