The Molecular Mechanism Study Of HDACI VPA On Epigenetic Regulation Of Schizophrenia

Schizophrenia is a complex mental disorder with high rates of disability, nonrecovery, and relapse. Both genetic and environmental factors are thought to play a significant role into the development of SCZ. Epigenetic modifications(such as histone modification and DNA methylation) are connection with gene-environment interactions, and more and more evidence that epigenetic changes involved in the pathophysiology of schizophrenia. Histone acetylation is regulated by the opposing effects of histone acetyltransferases(HATs) and deacetylases(HDACs). The histone acetylation enzyme for acetylation to inhibiting the role of gene expression may be involved in the pathogenesis of schizophrenia. Histone deacetylase inhibitor(HDACi) can inhibit histone acetylation transferase to regulate histone and histone acetylation level. There is emerging evidence that HDAC inhibition has a beneficial effect on learning and cognition in neurodegenerative dementia. VPA is a well-established neuroactive drug, which could used as anticonvulsant, mood stabilizer,also can inhances GABAergic transcription thereby reducing animal schizophrenic rats manic symptoms and depressive symptoms of the model. However, VPA and antipsychotic drugs used in combination to expand the influence of treatment hypothesis has not been established in the clinical trials, still need more verified experiment. Therefore, we hypothesized that HDACi VPA may be a potential drug to treatment schizophrenia, hower, the mechanism of VPA to schizophrenia epigenetic regulation has not clear yet, needing more laboratory worke to verify.ObjectiveTo explore GABA system gene(GABBR1、GABRA1、GAD1、GAD2)、LPL、SYN2、KCNJ4、TAC1、GRIA2 m RNA expression in four regions of PC(prefrontal cortex) 、AM(amygdala)、CPU(caudate-putamen)、HIP(hippocampus) with the expression in brain regions of the rat model of SCZ. At the same time, giving the HDACi VPA, alone or combination with antipsychotic chlorpromazine(CPZ), observing the changes in m RNA expression level of the above-mentioned candidate genes, infering whether the candidate genes are the target geen of the HDACi VPA; furthermore, preliminary discussed the impact of ionizing radiation on the VPA.MethodsSelect perinatal SD rats, established animal models of schizophrenia, HDACi VPA treatment given alone or in combination with antipsychotic CPZ, given the normal group and treatment group 2Gy PMV irradiation dose, irradiation conditions: The X-RAD 320 ix irradiator irradiating voltage 180 k V, current 20 m A, a single source target distance 70 cm, dose rate: 1.0Gy / min, irradiation way: body irradiate. The models were certified and cognition changes were detected by morris water maze test. The expression levels of candidate genes m RNA in the prefrontal cortex, amygdale, caudate-putamen and hippocampus tissues of the model rats with schizophrenia were tested by Real-Time PCR, SPSS16.0 software for statistical analysis.Results1、The study found that to the epigenetic model rats with schizophrenia PC、AM、CPU and HIP four brain regions, GABBR1 gene, GAD1 gene, GAD2 gene and SYN2 gene were significantly increased expression, giving HDACi valproic acid, the four genes m RNA expression in brain regions decreased or near normal levels.2、It was found that given 2 Gy dose ionizing radiation could increased the GAD1 gene, GAD2 gene, GRIA2 gene and SYN2 gene expression in the normal rats and PMV model rats.Concludion1、GABABR1 、GAD1 、GAD2 、SYN2 are likely to be the HDACi VPA targeting gene in epigenetic animal models brain of schizophrenia.2、Ionizing radiation could impact the HDACi VPA, but the exactly mechanism is still unclear, need a lot of study and experiments to explained.