title: Histone Modification of Nedd4 Ubiquitin Ligase Controls the Loss of AMPA Receptors and Cognitive Impairment Induced by Repeated Stress.
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.
  
  
  CONCLUSIONS
  Prolonged stress exposure can induce altered histone modification and transcriptional dysfunction, which may underlie the profound influence of stress in regulating brain functions. We report an important finding about the epigenetic mechanism controlling the detrimental effects of repeated stress on synaptic transmission and cognitive function. First, it has revealed the stress-induced alteration of key epigenetic regulators HDAC2 and Ehmt2, which determines the synaptic and behavioral effects of repeated stress. Second, it has uncovered the stress-induced histone modification of the target gene Nedd4, an E3 ligase that is critically involved in the ubiquitination and degradation of AMPA receptors and cognition. Third, it has provided the epigenetic approach, HDAC2 inhibition or knock-down, to rescue synaptic and cognitive functions in stressed animals.
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, and VA Western New York Healthcare System, Buffalo, New York 14215.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, and.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, and.
authors.forename: Janine B
authors.initials: JB
authors.lastname: Lee
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, and.
authors.forename: Jia
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, and.
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Duffney
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, and.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Matas
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, and VA Western New York Healthcare System, Buffalo, New York 14215 zhenyan@buffalo.edu.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D056827:Endosomal Sorting Complexes Required for Transport; D055785:Gene Knockdown Techniques; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D000075702:Nedd4 Ubiquitin Protein Ligases; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D017397:Prefrontal Cortex / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects; D013315:Stress, Psychological / Q000150:complications* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000235:genetics
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D018091:Receptors, AMPA; D011965:Receptors, Glucocorticoid; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618484:Nedd4 protein, rat; D044767:Ubiquitin-Protein Ligases; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2
keywords: AMPA receptors; E3 ubiquitin ligase; corticosterone; histone deacetylase; histone methyltransferase; histone modification