Department of Psychology, University of Kentucky, Lexington, KY, United States.
Department of Psychology, University of Kentucky, Lexington, KY, United States.
Alcohol. 2022 Sep;103:45-54. doi: 10.1016/j.alcohol.2022.07.007. Epub 2022 Aug 12.
Fetal Alcohol Spectrum Disorders (FASDs) are comprised of developmental, behavioral, and cognitive abnormalities caused by prenatal alcohol exposure, affecting an estimated 2%-5% of children and costing $4 billion annually in the United States. While some behavioral therapies help, the neurobiological mechanisms that underpin FASDs need further elucidation for development of effective pharmacotherapeutics. The role of the tau protein in the hippocampus is likely to be involved. Tau catalyzes microtubule polymerization in developing neurons. However, this function can become disrupted by hyperphosphorylation. Many of the cognitive deficits observed in neurodegenerative tauopathies overlap to some degree with what is observed in juvenile developmental disabilities, such as FASDs (e.g., selective memory, executive dysfunction). Thus, tau protein phosphorylation may be one important mechanism of dysfunction in FASDs. The purpose of this study is to provide an empirical basis for a tauopathic characterization of FASDs. To do so, hippocampal slices were extracted from rats at postnatal day 10 (PND10); hippocampal slices were then exposed to 5 days of 50-mM ethanol between 6 days in vitro (DIV) and 11DIV. Immunoblots were taken for Total and p-Tau (Threonine231) at 12DIV and 24DIV. Immunohistochemical fluorescent images were taken for p-Tau (Threonine231) at 12DIV and 24DIV. Separate p-Tau measures were taken for the cornu ammonis 1 (CA1), CA3, and dentate gyrus (DG). Total Tau protein expression remained unchanged between 12DIV and 24DIV regardless of ethanol condition. In the control group, longer DIV was associated with decreased p-Tau. However, in the ethanol-exposed group, p-Tau was sustained across DIV. This is the first study to show that ethanol exposure sustains tau Threonine231 phosphorylation in the perinatal hippocampus regardless of Total Tau expression. These findings could lead to innovative pharmacotherapeutic targets for the treatment of cognitive deficits seen in FASDs.
胎儿酒精谱系障碍（FASD）是由产前酒精暴露引起的发育、行为和认知异常，估计影响美国 2%-5%的儿童，每年造成 40 亿美元的损失。虽然一些行为疗法有帮助，但 FASD 的神经生物学机制需要进一步阐明，以开发有效的药物治疗方法。在海马体中，tau 蛋白的作用可能涉及其中。tau 蛋白在发育中的神经元中催化微管聚合。然而，这种功能可能会因过度磷酸化而受到干扰。在神经退行性 tau 病中观察到的许多认知缺陷在某种程度上与在青少年发育障碍中观察到的相似，如 FASD（例如，选择性记忆、执行功能障碍）。因此，tau 蛋白磷酸化可能是 FASD 功能障碍的一个重要机制。本研究旨在为 FASD 的 tau 病特征提供一个经验基础。为此，在出生后第 10 天（PND10）从大鼠中提取海马切片；然后在体外 6 天至 11 天（DIV）和 11 天至 11 天（DIV）之间，将海马切片暴露于 50mM 乙醇 5 天。在 12DIV 和 24DIV 时取总 tau 和磷酸化 tau（苏氨酸 231）的免疫印迹。在 12DIV 和 24DIV 时取磷酸化 tau（苏氨酸 231）的免疫组织化学荧光图像。分别对 Cornu Ammonis 1（CA1）、CA3 和齿状回（DG）进行 p-Tau 测量。无论乙醇条件如何，12DIV 和 24DIV 之间总 tau 蛋白表达不变。在对照组中，较长的 DIV 与 p-Tau 减少相关。然而，在乙醇暴露组中，p-Tau 在整个 DIV 中保持不变。这是第一项表明乙醇暴露无论总 tau 表达如何，都能维持围生期海马体 tau 苏氨酸 231 磷酸化的研究。这些发现可能为治疗 FASD 中观察到的认知缺陷提供创新的药物治疗靶点。
