title: Valproic acid, a histone deacetylase inhibitor, regulates cell proliferation in the adult zebrafish optic tectum.
abstract: BACKGROUND
  Valproic acid (VPA) has been used to treat epilepsy and bipolar disorder. Several reports have demonstrated that VPA functions as a histone deacetylase (HDAC) inhibitor. While VPA is known to cause teratogenic changes in the embryonic zebrafish brain, its effects on neural stem cells (NSCs) in both the embryonic and adult zebrafish are not well understood.
  
  
  RESULTS
  In this study, we observed a proliferative effect of VPA on NSCs in the embryonic hindbrain. In contrast, VPA reduced cell proliferation in the adult zebrafish optic tectum. Treatment with HDAC inhibitors showed a similar inhibitory effect on cell proliferation in the adult zebrafish optic tectum, suggesting that VPA reduces cell proliferation through HDAC inhibition. Cell cycle progression was also suppressed in the optic tectum of the adult zebrafish brain because of HDAC inhibition. Recent studies have demonstrated that HDAC inhibits the Notch signaling pathway; hence, adult zebrafish were treated with a Notch inhibitor. This increased the number of proliferating cells in the adult zebrafish optic tectum with down-regulated expression of her4, a target of Notch signaling.
  
  
  CONCLUSIONS
  These results suggest that VPA inhibits HDAC activity and upregulates Notch signaling to reduce cell proliferation in the optic tectum of adult zebrafish.
authors.affiliation: Department of Life Science and Medical Bio-Science, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Dozawa
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kono
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sato
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ito
authors.forename: Hideomi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohshima
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D020287:In Situ Nick-End Labeling; D058953:Neural Stem Cells / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013477:Superior Colliculi / Q000166:cytology* / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*; D015027:Zebrafish / Q000378:metabolism / Q000502:physiology*; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D017931:DNA Primers; D056572:Histone Deacetylase Inhibitors; D051880:Receptors, Notch; D014635:Valproic Acid; D029961:Zebrafish Proteins; C119433:her4.1 protein, zebrafish
keywords: HDAC; VPA; adult neurogenesis; optic tectum; zebrafish