Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
Int J Neuropsychopharmacol. 2012 Nov;15(10):1489-501. doi: 10.1017/S1461145711001672. Epub 2011 Nov 18.
Enriched environments (EEs) during development have been shown to influence adult behaviour. Environmental conditions during childhood may contribute to the onset and/or pathology of schizophrenia; however, it remains unclear whether EE might prevent the development of schizophrenia. Herein, we investigated the effects of EE during adolescence on phencyclidine (PCP)-induced abnormal behaviour, a proposed schizophrenic endophenotype. Male ICR mice (3 wk old) were exposed to an EE for 4 wk and then treated with PCP for 2 wk. The EE potentiated the acute PCP treatment-induced hyperlocomotion in the locomotor test and prevented chronic PCP treatment-induced impairments of social behaviour and recognition memory in the social interaction and novel object recognition tests. It also prevented the PCP-induced decrease of acetylated Lys9 in histone H3-positive cells and increase of the histone deacetylase (HDAC)5 level in the prefrontal cortex. To investigate whether the histone modification during adolescence might be critical for the effect of EE, 3-wk-old mice were first treated with sodium butyrate (SB; an HDAC inhibitor) for 4 wk and then treated with PCP for 2 wk. Chronic SB treatment during adolescence mimicked the effects of EE, including potentiation of hyperlocomotion induced by acute PCP treatment and prevention of social and cognitive impairments, decrease of acetylated Lys9 in histone H3-positive cells and increase of the HDAC5 level in the prefrontal cortex associated with chronic PCP treatment. Our results suggest that EEs prevent PCP-induced abnormal behaviour associated with histone deacetylation. EEs during childhood might prove to be a novel strategy for prophylaxis against schizophrenia.
丰富的环境（EEs）在发育过程中已被证明会影响成年后的行为。儿童时期的环境条件可能导致精神分裂症的发病和/或病理；然而，EE 是否可能预防精神分裂症的发展仍不清楚。在此，我们研究了青春期 EE 对苯环利定（PCP）诱导的异常行为的影响，这是一种拟议的精神分裂症内表型。雄性 ICR 小鼠（3 周龄）暴露于 EE 中 4 周，然后用 PCP 处理 2 周。EE 增强了急性 PCP 处理诱导的运动测试中的过度活跃，防止了慢性 PCP 处理引起的社会行为和识别记忆受损在社会互动和新物体识别测试中。它还防止了 PCP 诱导的组蛋白 H3 阳性细胞中乙酰化 Lys9 的减少和前额叶皮层中组蛋白去乙酰化酶（HDAC）5 水平的增加。为了研究青春期期间的组蛋白修饰是否对 EE 的作用至关重要，首先用丁酸钠（SB；HDAC 抑制剂）处理 3 周龄的小鼠 4 周，然后用 PCP 处理 2 周。青春期慢性 SB 处理模拟了 EE 的作用，包括增强急性 PCP 处理诱导的过度活跃以及预防社会和认知障碍、减少与慢性 PCP 处理相关的组蛋白 H3 阳性细胞中乙酰化 Lys9 和前额叶皮层中 HDAC5 水平的增加。我们的结果表明，EEs 可预防与组蛋白去乙酰化相关的 PCP 诱导的异常行为。儿童时期的 EEs 可能被证明是预防精神分裂症的一种新策略。
