| 1 | Nat. Neurosci. 2012 Sep 15: 1245-54 |
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| PMID | 22864611 |
| Title | HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. |
| Abstract | Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown. Here we found that chronic atypical antipsychotics downregulated the transcription of metabotropic glutamate 2 receptor (mGlu2, also known as Grm2), an effect that was associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurred in concert with a serotonin 5-HT(2A) receptor-dependent upregulation and increased binding of HDAC2 to the mGlu2 promoter. Virally mediated overexpression of HDAC2 in frontal cortex decreased mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevented the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augmented their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target for schizophrenia treatment. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 2 | Schizophr. Res. 2012 Feb 134: 260-6 |
| PMID | 22206711 |
| Title | Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders. |
| Abstract | To improve the understanding of psychotic abnormalities and their non-Mendelian inheritance patterns, the epigenetic regulation of the psychotic disorder-associated GABRB2, gene for the type A ?-aminobutyric acid receptor ?(2)-subunit, was investigated. Expression of GABRB2, and the epigenetic regulatory enzymes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) in mouse and postmortem human brains was analyzed using real-time PCR. Results showed that expression of GABRB2 isoforms significantly increased over time in both mouse and human, especially for the long splicing isoform. In the brains of non-psychiatric controls (CON), a significant positive correlation of GABRB2 expression with age was observed in individuals with MM genotypes of the single nucleotide polymorphisms (SNPs) rs187269 and rs1816072. This was reversed to a significant negative correlation in schizophrenics (SCZ). A similar reversal was also displayed by bipolar disorder (BPD) patients. In parallel, a significant co-variation of HDAC1 with GABRB2 expression observed in CON remained significant in BPD but not in SCZ; comparably, a significant co-variation of HDAC2 with GABRB2 expression observed in CON became non-significant in both SCZ and BPD. Moreover, co-variations of DNMT1 and DNMT3B with GABRB2, not observable in CON, became significant in BPD. These findings demonstrated that GABRB2 expression was under epigenetic regulation that varied with development, genotype and disease status, and these regulatory mechanisms were observably disrupted in SCZ and BPD. This study provided insight into the complex inheritance patterns of psychiatric disorders, and pointed to the involvement of epigenetic dysregulation in the disease process of major psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 3 | PLoS ONE 2013 -1 8: e71323 |
| PMID | 23967191 |
| Title | A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests. |
| Abstract | Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary--albeit often ineffective--treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 4 | Expert Rev Neurother 2013 Jan 13: 1-3 |
| PMID | 23253383 |
| Title | HDAC2 as a new target to improve schizophrenia treatment. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenics |
| 5 | Asia Pac Psychiatry 2013 Mar 5: 11-6 |
| PMID | 23857786 |
| Title | Associations of histone deacetylase-2 and histone deacetylase-3 genes with schizophrenia in a Chinese population. |
| Abstract | To explore the association between histone deacetylase-2 (HDAC2) and histone deacetylase-3 (HDAC3) gene polymorphisms and schizophrenia. A total of 208 family trios consisting of fathers, mothers and affected offspring with schizophrenia were recruited as our subjects. Four tag SNPs on HDAC2 (rs10499080, rs6568819, rs2499618 and rs13204445) and two tag SNPs on HDAC3 (rs11741808, rs2530223) genes were selected. The Mass ARRAY Assay Design software (Sequenom) was used to design amplification and allele specific extension primers. The Hardy-Weinberg equilibrium (HWE) for genotypic distributions was tested using the chi-square goodness-of-fit test. Allelic association for a single tag SNP was analyzed by using family-based association tests including the haplotype-based haplotype relative risk (HHRR) test and the transmission disequilibrium test (TDT). The genotypic distributions of HDAC2 SNPs rs6568819, rs2499618 and rs13204445 and HDAC3 SNPs rs11741808 and rs2530223 were all in Hardy-Weinberg equilibrium (P > 0.05). HHRR analysis revealed no associations between the SNPs and schizophrenia (P > 0.05). In addition, the TDT did not show any significant associations between HDAC2 and HDAC3 SNPs and schizophrenia (P > 0.05). HDAC2 and HDAC3 might not be associated with schizophrenia in the Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 6 | Trends Neurosci. 2015 Aug 38: 506-16 |
| PMID | 26148747 |
| Title | Positive allosteric modulators of metabotropic glutamate 2 receptors in schizophrenia treatment. |
| Abstract | The past two decades have witnessed a rise in the 'NMDA receptor hypofunction' hypothesis for schizophrenia, a devastating disorder that affects around 1% of the population worldwide. A variety of presynaptic, postsynaptic, and regulatory proteins involved in glutamatergic signaling have thus been proposed as potential therapeutic targets. This review focuses on positive allosteric modulation of metabotropic glutamate 2 receptors (mGlu2Rs) and discusses how recent preclinical epigenetic data may provide a molecular explanation for the discrepant results of clinical studies, further stimulating the field to exploit the promise of mGlu2R as a target for schizophrenia treatment. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 7 | Pharmacol Rep 2015 Dec 67: 1124-9 |
| PMID | 26481530 |
| Title | Valproic acid (VPA) reduces sensorimotor gating deficits and HDAC2 overexpression in the MAM animal model of schizophrenia. |
| Abstract | Evidence indicates that the disruption of epigenetic processes might play an important role in the development of schizophrenia symptoms. The present study investigated the role of histone acetylation in the development of sensorimotor gating deficits in a neurodevelopmental model of schizophrenia based on prenatal administration of methylazoxymethanol (MAM) at embryonic day 17. Valproic acid (VPA), an inhibitor of class I histone deacetylases, was administered (250 mg/kg, twice a day for 7 consecutive days) in early adolescence (23rd-29th day) or early adulthood (63rd-69th day) to rats. The effect of VPA treatment on the sensorimotor gating deficits induced by prenatal MAM administration was analyzed in adult rats at postnatal day 70 (P70). In addition, the effects of VPA administration (at the same doses) on MAM-induced changes in the levels of histone H3 acetylation at lysine 9 (H3K9ac) and histone deacetylase 2 (HDAC2) in the medial prefrontal cortex (mPFC) were determined at P70 using Western blot. VPA administration in either adolescence or early adulthood prevented the sensorimotor gating deficits induced by MAM. However, VPA administration in early adolescence or early adulthood did not alter H3K9ac levels induced by MAM. In contrast, VPA administration in either adolescence or adulthood prevented the increase in HDAC2 level evoked by MAM. Prenatal MAM administration impaired histone acetylation in the mPFC, which might be involved in the development of some of the neurobehavioral deficits (i.e., sensorimotor gating deficits) associated with schizophrenia. Blockade of HDAC2 might prevent the disruption of sensorimotor gating in adulthood. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 8 | J. Hum. Genet. 2015 Sep 60: 479-84 |
| PMID | 26063464 |
| Title | Genetic analysis of common variants in the HDAC2 gene with schizophrenia susceptibility in Han Chinese. |
| Abstract | schizophrenia (SCZ) is a complex psychiatric disorder that is strongly influenced by a genetic component. Recent studies suggested that histone deacetylases (HDACs) might increase the expression of several key genes in the brain and may also be associated with susceptibility to SCZ. Among human HDACs, HDAC2 is a critical modulator of gene regulation. Here, we designed a two-stage case-control study to thoroughly examine the association between the HDAC2 gene and SCZ. A total of 19 common single-nucleotide polymorphisms (SNPs) in the region of the HDAC2 gene were analyzed in the test group of 1430 patients and 2862 matched healthy controls. A comparison of the genotype and allele frequencies of the SNPs between cases and controls revealed that three SNPs, rs13212283, rs6568819 and rs9488289, were nominally associated with SCZ. However, we failed to observe any association between these SNPs and SCZ in the validation group consisting of 896 cases and 1815 matched healthy controls. Furthermore, haplotypic analysis also confirmed the negative results. Our results provide preliminary evidence that HDAC2 may not confer susceptibility to SCZ in Han Chinese. Additional genetic studies from a large population are required to obtain more conclusive results. |
| SCZ Keywords | schizophrenia, schizophrenics |