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孕期暴露于丙戊酸所致自闭症样大鼠脑内 Tau 蛋白水平及磷酸化状态的改变

Alterations in Tau Protein Level and Phosphorylation State in the Brain of the Autistic-Like Rats Induced by Prenatal Exposure to Valproic Acid.

作者信息

Gąssowska-Dobrowolska Magdalena, Kolasa-Wołosiuk Agnieszka, Cieślik Magdalena, Dominiak Agnieszka, Friedland Kristina, Adamczyk Agata

机构信息

Department of Cellular Signalling, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.

Department of Histology and Embryology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland.

出版信息

Int J Mol Sci. 2021 Mar 22;22(6):3209. doi: 10.3390/ijms22063209.

DOI:10.3390/ijms22063209
PMID:33809910
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8004207/
Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficient social interaction and communication besides repetitive, stereotyped behaviours. A characteristic feature of ASD is altered dendritic spine density and morphology associated with synaptic plasticity disturbances. Since microtubules (MTs) regulate dendritic spine morphology and play an important role in spine development and plasticity the aim of the present study was to investigate the alterations in the content of neuronal α/β-tubulin and Tau protein level as well as phosphorylation state in the valproic acid (VPA)-induced rat model of autism. Our results indicated that maternal exposure to VPA induces: (1) decrease the level of α/β-tubulin along with Tau accumulation in the hippocampus and cerebral cortex; (2) excessive Tau phosphorylation and activation of Tau-kinases: CDK5, ERK1/2, and p70S6K in the cerebral cortex; (3) up-regulation of mTOR kinase-dependent signalling in the hippocampus and cerebral cortex of adolescent rat offspring. Moreover, immunohistochemical staining showed histopathological changes in neurons (chromatolysis) in both analysed brain structures of rats prenatally exposed to VPA. The observed changes in Tau protein together with an excessive decrease in α/β-tubulin level may suggest destabilization and thus dysfunction of the MT cytoskeleton network, which in consequence may lead to the disturbance in synaptic plasticity and the development of autistic-like behaviours.

摘要

自闭症谱系障碍（ASD）是一种神经发育疾病，其特征除了重复、刻板行为外，还包括社交互动和沟通缺陷。ASD的一个特征是树突棘密度和形态的改变，这与突触可塑性障碍有关。由于微管（MTs）调节树突棘形态，并在树突棘发育和可塑性中发挥重要作用，因此本研究的目的是调查在丙戊酸（VPA）诱导的自闭症大鼠模型中神经元α/β-微管蛋白含量、Tau蛋白水平以及磷酸化状态的变化。我们的结果表明，母体暴露于VPA会导致：（1）海马体和大脑皮层中α/β-微管蛋白水平降低以及Tau蛋白积累；（2）大脑皮层中Tau过度磷酸化以及Tau激酶CDK5、ERK1/2和p70S6K的激活；（3）青春期大鼠后代的海马体和大脑皮层中mTOR激酶依赖性信号上调。此外，免疫组织化学染色显示，产前暴露于VPA的大鼠的两个分析脑结构中的神经元出现组织病理学变化（染色质溶解）。观察到的Tau蛋白变化以及α/β-微管蛋白水平的过度降低可能表明MT细胞骨架网络不稳定，进而功能失调，这可能会导致突触可塑性紊乱和自闭症样行为的发展。

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