Valproic acid (VPA) reduces sensorimotor gating deficits and HDAC2 overexpression in the MAM animal model of schizophrenia
Valproic acid (VPA) reduces sensorimotor gating deficits and HDAC2 overexpression in the MAM animal model of schizophrenia
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DOI：
10.1016/j.pharep.2015.04.004
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发表时间：
2015-01-01
影响因子：
4.4
通讯作者：
Mackowiak, Marzena
中科院分区：
文献类型：
--
作者：
Bator, Ewelina;Latusz, Joachim;Mackowiak, Marzena
背景：有证据表明，表观遗传过程的破坏可能在精神分裂症症状的发展中起重要作用。本研究通过在胚胎17天产前给予甲基偶氮氧甲醇（MAM）的精神分裂症神经发育模型，探讨组蛋白乙酰化在感觉运动门控缺陷发生中的作用。方法：给予丙戊酸（VPA），一种I类组蛋白脱乙酰酶抑制剂，（250 mg/kg，每天两次，连续7天）对大鼠在青春期早期（第23 - 29天）或成年早期（第63 - 69天）。在出生后第70天（P70）的成年大鼠中分析VPA处理对产前MAM给药诱导的感觉运动门控缺陷的影响。此外，VPA管理（在相同的剂量）对MAM诱导的组蛋白H3乙酰化水平的变化在赖氨酸9（H3 K9 ac）和组蛋白去乙酰化酶2（HDAC 2）在内侧前额叶皮层（mPFC）的影响，在P70使用Western blot测定。然而，在青春期早期或成年早期给予VPA不会改变MAM诱导的H3 K9 ac水平。相反，在青春期或成年期给予VPA可防止MAM引起的HDAC 2水平升高。结论：产前给予MAM可损害mPFC中的组蛋白乙酰化，这可能与某些神经行为缺陷的发生有关（即，感觉运动门控缺陷）与精神分裂症相关。HDAC 2的阻断可能会防止成年期感觉运动门控的破坏。(C)2015年波兰科学院药理学研究所。由爱思唯尔股份有限公司出版All rights reserved.
Background: 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.Methods: 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.Results: 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.Conclusions: 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. (C) 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.