REARRANGEMENT OF THE DENDRITIC MORPHOLOGY IN LIMBIC REGIONS AND ALTERED EXPLORATORY BEHAVIOR IN A RAT MODEL OF AUTISM SPECTRUM DISORDER
REARRANGEMENT OF THE DENDRITIC MORPHOLOGY IN LIMBIC REGIONS AND ALTERED EXPLORATORY BEHAVIOR IN A RAT MODEL OF AUTISM SPECTRUM DISORDER
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DOI：
10.1016/j.neuroscience.2013.03.030
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发表时间：
2013-06-25
期刊：
影响因子：
3.3
通讯作者：
Flores, G.
中科院分区：
文献类型：
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作者：
Bringas, M. E.;Carvajal-Flores, F. N.;Flores, G.
丙戊酸（VPA）是一种广泛用于治疗癫痫、双相情感障碍和偏头痛的组蛋白去乙酰化酶阻滞剂;妊娠期间服用VPA会增加儿童患自闭症谱系障碍（ASD）的风险。因此，产前VPA暴露已成为ASD的啮齿动物模型。在本研究中，我们的目的是探讨VPA的产前管理的影响，（500 mg/kg）对新环境中的探索行为和自发活动，以及对三个不同年龄的前额叶皮层（PFC）、海马、丘脑核（NAcc）和基底外侧杏仁核（BLA）中的神经元形态重排的影响：断奶后即刻（出生后第21天[PD 21]）、青春期前（PD 35）和青春期后（PD 70）年龄。在PD 21和PD 70时，在VPA动物的新环境中观察到过度运动。有趣的是，在PD 70时通过孔板试验评估的探索行为显示，与溶媒给药动物相比，VPA-动物的头浸频率降低，但持续时间增加。此外，在PD 70时，产前VPA给药动物的首次头部下沉潜伏期较长。树突棘密度的定量形态学分析显示，在PD 70的PFC，背侧海马和BLA的棘数量减少，在NAcc和腹侧海马的树突棘密度增加，在产前VPA处理的大鼠。此外，在PD 70时，在NAcc、PFC第3层和BLA中观察到神经元树枝化增加，腹侧和背侧海马中神经元树枝化回缩。我们的研究结果扩展了在ASD模型中检测到的行为改变（探索行为）的列表，并表明VPA行为表型伴随着以前未描述的边缘区形态学重排。(C)2013年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Valproic acid (VPA) is a blocker of histone deacetylase widely used to treat epilepsy, bipolar disorders, and migraine; its administration during pregnancy increases the risk of autism spectrum disorder (ASD) in the child. Thus, prenatal VPA exposure has emerged as a rodent model of ASD. In the present study, we aimed to investigate the effect of prenatal administration of VPA (500 mg/kg) at E12.5 on the exploratory behavior and locomotor activity in a novel environment, as well as on neuronal morphological rearrangement in the prefrontal cortex (PFC), in the hippocampus, in the nucleus accumbens (NAcc), and in the basolateral amygdala (BLA) at three different ages: immediately after weaning (postnatal day 21 [PD21]), prepubertal (PD35) and postpubertal (PD70) ages. Hyper-locomotion was observed in a novel environment in VPA animals at PD21 and PD70. Interestingly, exploratory behavior assessed by the hole board test at PD70 showed a reduced frequency but an increase in the duration of head-dippings in VPA-animals compared to vehicle-treated animals. In addition, the latency to the first head-dip was longer in prenatal VPA-treated animals at PD70. Quantitative morphological analysis of dendritic spine density revealed a reduced number of spines at PD70 in the PFC, dorsal hippocampus and BLA, with an increase in the dendritic spine density in NAcc and ventral hippocampus, in prenatal VPA-treated rats. In addition, at PD70 increases in neuronal arborization were observed in the NAcc, layer 3 of the PFC, and BLA, with retracted neuronal arborization in the ventral and dorsal hippocampus. Our results extend the list of altered behaviors (exploratory behavior) detected in this model of ASD, and indicate that the VPA behavioral phenotype is accompanied by previously undescribed morphological rearrangement in limbic regions. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.