title: Prefrontal cortical dysfunction after overexpression of histone deacetylase 1.
abstract: BACKGROUND
  Postmortem brain studies have shown that HDAC1-a lysine deacetylase with broad activity against histones and nonhistone proteins-is frequently expressed at increased levels in prefrontal cortex (PFC) of subjects diagnosed with schizophrenia and related disease. However, it remains unclear whether upregulated expression of Hdac1 in the PFC could affect cognition and behavior.
  
  
  METHODS
  Using adeno-associated virus, an Hdac1 transgene was expressed in young adult mouse PFC, followed by behavioral assays for working and long-term memory, repetitive activity, and response to novelty. Prefrontal cortex transcriptomes were profiled by microarray. Antipsychotic drug effects were explored in mice treated for 21 days with haloperidol or clozapine.
  
  
  RESULTS
  Hdac1 overexpression in PFC neurons and astrocytes resulted in robust impairments in working memory, increased repetitive behaviors, and abnormal locomotor response profiles in novel environments. Long-term memory remained intact. Over 300 transcripts showed subtle but significant changes in Hdac1-overexpressing PFC. Major histocompatibility complex class II (MHC II)-related transcripts, including HLA-DQA1/H2-Aa, HLA-DQB1/H2-Ab1, and HLA-DRB1/H2-Eb1, located in the chromosome 6p21.3-22.1 schizophrenia and bipolar disorder risk locus, were among the subset of genes with a more robust (>1.5-fold) downregulation in expression. Hdac1 levels declined during the course of normal PFC development. Antipsychotic drug treatment, including the atypical clozapine, did not affect Hdac1 levels in PFC but induced expression of multiple MHC II transcripts.
  
  
  CONCLUSIONS
  Excessive HDAC1 activity, due to developmental defects or other factors, is associated with behavioral alterations and dysregulated expression of MHC II and other gene transcripts in the PFC.
authors.affiliation: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester Massachusetts.
authors.forename: Mira
authors.initials: M
authors.lastname: Jakovcevski
authors.forename: Rahul
authors.initials: R
authors.lastname: Bharadwaj
authors.forename: Juerg
authors.initials: J
authors.lastname: Straubhaar
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.forename: David P
authors.initials: DP
authors.lastname: Gavin
authors.forename: Igor
authors.initials: I
authors.lastname: Jakovcevski
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Mitchell
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology; D015536:Down-Regulation; D005106:Exploratory Behavior / Q000502:physiology*; D005802:Genes, MHC Class II / Q000235:genetics; D006220:Haloperidol / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D056284:Histone Deacetylase 1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D057567:Memory, Long-Term / Q000502:physiology*; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000503:physiopathology*; D013239:Stereotyped Behavior / Q000502:physiology; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation
chemical_list: D000949:Histocompatibility Antigens Class II; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D003024:Clozapine; D006220:Haloperidol
keywords: Bipolar disorder; gene expression; major histocompatibility complex II; prefrontal cortex; protein deacetylase; schizophrenia