title: A Mercaptoacetamide-Based Class II Histone Deacetylase Inhibitor Increases Dendritic Spine Density via RasGRF1/ERK Pathway.
abstract: BACKGROUND
  The accumulation of amyloid-β (Aβ) leads to the loss of dendritic spines and synapses, which is hypothesized to cause cognitive impairments in Alzheimer's disease (AD) patients. In our previous study, we demonstrated that a novel mercaptoacetamide-based class II histone deacetylase inhibitor (HDACI), known as W2, decreased Aβ levels and improved learning and memory in mice. However, the underlying mechanism of this effect is unknown.
  
  
  OBJECTIVE
  Because dendritic spine formation is associated with cognitive performance, here we investigated whether HDACI W2 regulates dendritic spine density and its molecular mechanism of action.
  
  
  METHODS
  To examine the effect of HDACI W2 on dendritic spine density, we conducted morphological analysis of dendritic spines using GFP transfection and Golgi staining. In addition, to determine the molecular mechanism of W2 effects on spines, we measured the levels of mRNAs and proteins involved in the Ras signaling pathway using quantitative real-time PCR, immunocytochemistry, and western analysis.
  
  
  RESULTS
  We found that HDACI W2 altered dendritic spine density and morphology in vitro and in vivo. Additionally, W2 increased the mRNA or protein levels of Ras GRF1 and phospho-ERK. Moreover, knockdown of RasGRF1 and inhibition of ERK activity prevented the W2-mediated spinogenesis in primary hippocampal neurons.
  
  
  CONCLUSIONS
  Our Class II-selective HDACI W2 promotes the formation and growth of dendritic spines in a RasGRF1 and ERK dependent manner in primary hippocampal neurons.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Song
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: You Me
authors.initials: YM
authors.lastname: Sung
authors.affiliation: Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Dong-gu, Daegu, Korea.
authors.forename: Jin Han
authors.initials: JH
authors.lastname: Nam
authors.affiliation: Department of Neuroscience, Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chung
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Moffat
authors.affiliation: Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Mira
authors.initials: M
authors.lastname: Jung
authors.affiliation: Department of Pharmacology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Daniel T S
authors.initials: DT
authors.lastname: Pak
authors.affiliation: Department of Neuroscience, Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.|Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Dong-gu, Daegu, Korea.
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Hoe
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D049229:Dendritic Spines / Q000187:drug effects* / Q000201:enzymology; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013864:Thioglycolates / Q000494:pharmacology*; D014162:Transfection; D020666:ras-GRF1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000081:Acetamides; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; C513037:Rasgrf1 protein, mouse; C525926:Rasgrf1 protein, rat; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013864:Thioglycolates; D020666:ras-GRF1; D049452:Green Fluorescent Proteins
keywords: Alzheimer’s disease; HDAC inhibitor; dendritic spine; ras signaling