Prefrontal cortical dysfunction after overexpression of histone deacetylase 1

TY - JOUR

T1 - Prefrontal cortical dysfunction after overexpression of histone deacetylase 1

AU - Jakovcevski, Mira

AU - Bharadwaj, Rahul

AU - Straubhaar, Juerg

AU - Gao, Guangping

AU - Gavin, David P

AU - Jakovcevski, Igor

AU - Mitchell, Amanda C

AU - Akbarian, Schahram

N1 - © 2013 Society of Biological Psychiatry.

PY - 2013/11/1

Y1 - 2013/11/1

N2 - 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.

AB - 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.

KW - Animals

KW - Astrocytes

KW - Clozapine

KW - Down-Regulation

KW - Exploratory Behavior

KW - Genes, MHC Class II

KW - Haloperidol

KW - Histocompatibility Antigens Class II

KW - Histone Deacetylase 1

KW - Memory, Long-Term

KW - Memory, Short-Term

KW - Mice

KW - Mice, Transgenic

KW - Neurons

KW - Prefrontal Cortex

KW - Stereotyped Behavior

KW - Transcriptome

KW - Up-Regulation

U2 - 10.1016/j.biopsych.2013.03.020

DO - 10.1016/j.biopsych.2013.03.020

M3 - SCORING: Journal article

C2 - 23664640

VL - 74

SP - 696

EP - 705

JO - BIOL PSYCHIAT

JF - BIOL PSYCHIAT

SN - 0006-3223

IS - 9

ER -