Prefrontal cortical dysfunction after overexpression of histone deacetylase 1
Brudnick Neuropsychiatric Research Institute; Program in Molecular Medicine; Gene Therapy Center and Vector Core
Animals; Astrocytes; Clozapine; Down-Regulation; Exploratory Behavior; Genes, MHC Class II; Haloperidol; Histocompatibility Antigens Class II; Histone Deacetylase 1; Memory, Long-Term; Memory, Short-Term; Mice; Mice, Transgenic; Neurons; Prefrontal Cortex; Stereotyped Behavior; Transcriptome; Up-Regulation
Mental Disorders | Molecular and Cellular Neuroscience | Molecular Genetics | Psychiatry | Psychiatry and Psychology
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.
DOI of Published Version
Biol Psychiatry. 2013 Nov 1;74(9):696-705. doi: 10.1016/j.biopsych.2013.03.020. Epub 2013 May 7. Link to article on publisher's site
Jakovcevski, Mira; Bharadwaj, Rahul; Straubhaar, Juerg R.; Gao, Guangping; Gavin, David P.; Jakovcevski, Igor; Mitchell, Amanda C.; and Akbarian, Schahram, "Prefrontal cortical dysfunction after overexpression of histone deacetylase 1" (2013). University of Massachusetts Medical School Faculty Publications. 815.