Prenatal alcohol exposure alters p35, CDK5 and GSK3β in the medial frontal cortex and hippocampus of adolescent mice.
Prenatal alcohol exposure alters p35, CDK5 and GSK3β in the medial frontal cortex and hippocampus of adolescent mice.
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DOI：
10.1016/j.toxrep.2014.08.005
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发表时间：
2014
影响因子：
--
通讯作者：
Allan, Andrea M
中科院分区：
文献类型：
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作者：
Goggin, Samantha L;Caldwell, Kevin K;Cunningham, Lee Anna;Allan, Andrea M
使用中度产前酒精暴露（PAE）的体内啮齿动物模型来研究对青少年大脑的影响。阐明CDK 5和GSK 3 β发育变化对于理解PAE相关缺陷非常重要。PAE增加海马p35和降低GSK 3 β水平，以及增加GSK 3 β Ser 9和Tyr 216磷酸化。PAE增加额叶皮质GSK 3 β，同时降低GSK 3 β Tyr 216磷酸化，并降低p35和CDK 5。胎儿酒精谱系障碍（FASD）是可预防的精神发育迟滞的头号原因。估计有2-5%的儿童被诊断为FASD。虽然众所周知，产前接触酒精的儿童在以后的生活中会出现认知缺陷和精神疾病的发病率较高，但这些异常的潜在途径仍然不确定。GSK 3 β和CDK 5是蛋白激酶，它们是大量信号级联的汇聚点，包括控制对学习和记忆至关重要的细胞过程的信号级联。我们研究了GSK 3 β和CDK 5水平是否受到适度产前酒精暴露（PAE）的影响，特别是在青春期小鼠的海马和内侧额叶皮层。在本工作中，我们利用免疫印迹技术证明中度CAE增加海马p35和β-连环蛋白，降低GSK 3 β的总水平，同时增加GSK 3 β Ser 9和Tyr 216磷酸化。有趣的是，在内侧额叶皮质中观察到不同的改变，其中p35和CDK 5降低，总GSK 3 β增加，伴随着酶的Tyr 216减少。这些结果表明，在青春期激酶失调可能是一个重要的影响因素，PAE对海马和内侧额叶皮质功能的影响，并通过扩展，这些激酶的全球调制可能会产生不同的影响，这取决于大脑区域。
An in vivo rodent model of moderate prenatal alcohol exposure (PAE) was used to investigate effects on the adolescent brain. Elucidating CDK5 and GSK3β developmental changes is important to understanding PAE-related deficits. PAE increased hippocampal p35 and decreased GSK3β levels, as well as increased GSK3β Ser9 and Tyr216 phosphorylation. PAE increased frontal cortical GSK3β, while decreasing GSK3β Tyr216 phosphorylation, and decreased p35 and CDK5. Fetal alcohol spectrum disorders (FASDs) are the number one cause of preventable mental retardation. An estimated 2–5% of children are diagnosed as having a FASD. While it is known that children prenatally exposed to alcohol experience cognitive deficits and a higher incidence of psychiatric illness later in life, the pathways underlying these abnormalities remain uncertain. GSK3β and CDK5 are protein kinases that are converging points for a vast number of signaling cascades, including those controlling cellular processes critical to learning and memory. We investigated whether levels of GSK3β and CDK5 are affected by moderate prenatal alcohol exposure (PAE), specifically in the hippocampus and medial frontal cortex of the adolescent mouse. In the present work we utilized immunoblotting techniques to demonstrate that moderate PAE increased hippocampal p35 and β-catenin, and decreased total levels of GSK3β, while increasing GSK3β Ser9 and Tyr216 phosphorylation. Interestingly, different alterations were seen in the medial frontal cortex where p35 and CDK5 were decreased and increased total GSK3β was accompanied by reduced Tyr216 of the enzyme. These results suggest that kinase dysregulation during adolescence might be an important contributing factor to the effects of PAE on hippocampal and medial frontal cortical functioning; and by extension, that global modulation of these kinases may produce differing effects depending on brain region.