Abstract
Schizophrenia (SZ) is associated with GABA neuron dysfunction in the hippocampus, particularly the stratum oriens of sector CA3/2. A gene expression profile analysis of human postmortem hippocampal tissue followed by a network association analysis had shown a number of genes differentially regulated in SZ, including the epigenetic factors HDAC1 and DAXX. To characterize the contribution of these factors to the developmental perturbation hypothesized to underlie SZ, lentiviral vectors carrying short hairpin RNA interference (shRNAi) for HDAC1 and DAXX were used. In the hippocampal GABA neuron culture model, HiB5, transduction with HDAC1 shRNAi showed a 40% inhibition of HDAC1 mRNA and a 60% inhibition of HDAC1 protein. GAD67, a enzyme associated with GABA synthesis, was increased twofold (mRNA); the protein showed a 35% increase. The expression of DAXX, a co-repressor of HDAC1, was not influenced by HDAC1 inhibition. Transduction of HiB5 cells with DAXX shRNAi resulted in a 30% inhibition of DAXX mRNA that translated into a 90% inhibition of DAXX protein. GAD1 mRNA was upregulated fourfold, while its protein increased by ~30%. HDAC1 expression was not altered by inhibition of DAXX. However, a physical interaction between HDAC1 and DAXX was demonstrated by co-immunoprecipitation. Inhibition of HDAC1 or DAXX increased expression of egr-1, transcription factor that had previously been shown to regulate the GAD67 promoter. Our in vitro results point to a key role of both HDAC1 and DAXX in the regulation of GAD67 in GABAergic HiB5 cells, strongly suggesting that these epigenetic/transcription factors contribute to mechanisms underlying GABA cell dysfunction in SZ.
Highlights
Schizophrenia (SZ) is a debilitating mental disorder, which affects approximately 1% of the world population and is responsible for about 3% of the disease-related economic burden.[1]
Our results demonstrate that the epigenetic factors histone deacetylase 1 (HDAC1) and DAXX are co-localized with each other in GABA neurons in human hippocampal stratum oriens (SO) of CA3/2 and have the ability to regulate the expression of the GAD1 gene in hippocampal neurons in vitro
The findings reported suggest the products of these two genes could play a central role in the normal and abnormal regulation of GABA neuron function in SZ, since they are both significantly upregulated at a locus where GAD67 expression is reduced in this disorder
Summary
Schizophrenia (SZ) is a debilitating mental disorder, which affects approximately 1% of the world population and is responsible for about 3% of the disease-related economic burden.[1]. Using a combination of laser microdissection and gene expression analysis of human postmortem hippocampal tissue, a previous network association analysis detected a number of genes associated with the regulation of GAD67 expression that were abnormally regulated in SZ compared with normal controls.[8,9,10] This abnormal expression of genes within the network was found in the hippocampal stratum oriens (SO) of sector CA3/2. Two of the genes (that is, HDAC1 and DAXX) are co-repressors associated with epigenetic regulation that help to control promoter histone acetylation reactions involved in regulating GAD67.12–15
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
