Histone deactylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: Analysis of the National Brain Databank microarray collection

Abstract

Histone deactylase enzymes are responsible for the deacetylation of histone tails, and consequently influence gene regulation through their ability to modify chromatin structure surrounding promoter regions. We analyzed the microarray collection of the National Brain Databank to investigate differential expression of these enzymes in the prefrontal cortices of control, schizophrenia and bipolar subjects. HDAC1 expression levels were significantly higher in schizophrenia versus normal subjects. The mRNA expression level of an epigenetically regulated gene GAD67 was strongly and negatively correlated with the mRNA expression levels of HDAC1, HDAC3 and HDAC4 levels. These findings provide additional support for the proposal that epigenetic factors are operative in the brain pathology of patients with schizophrenia.

HDAC1 links early life stress to schizophrenia-like phenotypes

“…S1A). These data confirm previous results showing that Hdac1 is upregulated in postmortem brain samples from patients with schizophrenia (21,22) and provide further evidence that HDAC1 might play a role in the pathogenesis of neuropsychiatric diseases. Because deletion or overexpression of Hdac1 in all neurons of the mouse brain from prenatal stages did not cause any behavioral changes (23), we speculated that elevated HDAC1 levels in patients with schizophrenia may be due to environmental risk factors that drive Hdac1 expression in the postnatal brain, thereby limiting the effect of compensatory processes.…”

“…Our findings confirm previous studies that reported elevated Hdac1 expression in patients with schizophrenia (21,22). Together with our observation that overexpression of HDAC1 in neurons of the mPFC of mice leads to schizophrenia-like phenotypes, these data provide solid evidence for a role of HDAC in the pathogenesis of schizophrenia.…”

“…These data have to be interpreted with care, however, because besides its action on HDACs, valproate affects many other cellular processes (20). Postmortem analysis of human brain tissue suggested that Hdac1 levels are elevated in the prefrontal cortex and hippocampus of patients with schizophrenia (21,22). It was therefore surprising that mutant mice either lacking…”

Growth Arrest and DNA-Damage-Inducible, Beta (GADD45b)-Mediated DNA Demethylation in Major Psychosis

“…It has been suggested that subjects with psychosis have histone marks characteristic of a restrictive chromatin state , such as reduced acetylated histone 3 , increased dimethylated lysine 9 of histone 3 (Gavin et al, 2009b), reduced methylated lysine 4 of histone 3 in female schizophrenics , and increased HDAC1 expression (Benes et al, 2007;Sharma et al, 2008). Although, Akbarian et al (2005) reported increases in an 'open' histone mark associated with reduced metabolic gene expression in SZ (Akbarian et al, 2005).…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Notably, as discussed above, HDAC1 regulates extinction learning via a mechanism involving H3K9 deacetylation and the subsequent trimethylation of target genes [185]. Interestingly, HDAC1 was up-regulated in postmortem brain samples from schizophrenic patients [223,224]. Using a pharmacological approach with the PCAF activator SPV106 and the PCAF inhibitor (H3-CoA-20-Tat), these authors demonstrated that PCAF activity facilitated the formation of fear extinction memory, but was not essential for fear acquisition [219].…”