Deficient Neuronal Glucose Transport Underlies Cortical Hyperexcitability in Mouse Models of Huntington’s Disease

摘要 葡萄糖是大脑中主要和优选的能量底物。在静息状态下，葡萄糖被吸收到 葡萄糖转运蛋白3（GLUT3）。然而，在亨廷顿病（HD）中，一种遗传性的、致命的、 由亨廷顿基因突变引起的神经退行性疾病，其特征是异常的 运动，以及认知和精神症状，脑能量代谢和GLUT3表达 显著减少。我们小组和其他人最近的研究也强调了 HD的神经发育成分特别是，我们已经报告了大脑结构异常， HD模型小鼠的皮质，这让人想起皮质发育的畸形。我们假设 在HD中，GLUT 3缺陷引起异常脑发育，导致皮质过度兴奋和进行性 出现症状。本提案旨在研究，在幼年和成年发病的小鼠 HD模型，GLUT 3在皮质发育中的作用，如果被证明有缺陷，则逆转这种缺陷， 防止表型的发展。有两个具体目标：目标1将主要研究GLUT 3 在发育中的HD小鼠中表达，从胚胎到成年阶段。目标2将使用遗传策略来探索 GLUT3的表达不足或过度如何影响疾病进展的发展。我们已经生成 并描述了GLUT3缺陷小鼠模型，对于这个项目，我们将创建一个新的GLUT3 过表达小鼠，其将与HD小鼠杂交。我们希望看到HD症状的改善 在皮质神经元中GLUT 3过表达的小鼠中。具体读数包括分子、行为和 电生理学技术，我们的实验室对此非常精通。这个项目是创新的， 葡萄糖转运在HD中的作用尚未充分研究，特别是在大脑发育期间。同样高度 重要的是发现了在早期发育过程中改善葡萄糖转运到大脑的新策略 可能是有益的，希望能起到预防作用

ABSTRACT Glucose is the main and preferred energy substrate in the brain. In resting conditions, glucose is taken up into neurons by the glucose transporter 3 (GLUT3). However, in Huntington’s disease (HD), a genetic, fatal, neurodegenerative disorder caused by a mutation in the Huntingtin gene and characterized by abnormal movements, as well as cognitive and psychiatric symptoms, brain energy metabolism and GLUT3 expression are significantly reduced. Recent studies by our group and others also emphasize the presence of a neurodevelopmental component in HD. In particular, we have reported structural abnormalities in the cerebral cortex of HD model mice, which are reminiscent of malformations of cortical development. We hypothesize that in HD, GLUT3 deficits cause abnormal brain development leading to cortical hyperexcitability and progressive emergence of symptoms. The present proposal is designed to examine, in juvenile and adult-onset mouse models of HD, the role of GLUT3 in cortical development and, if proven deficient, to reverse this deficiency and prevent development of the phenotype. There are two specific aims: Aim 1 will examine, primarily, GLUT3 expression in developing HD mice, from embryonic to adult stages. Aim 2 will use genetic strategies to explore how under- or over-expression of GLUT3 affects the development of disease progression. We have generated and characterized GLUT3-deficient mouse models, and for this project we will create a new line of GLUT3 overexpressing mice, which will be crossed with HD mice. We expect to see an improvement of HD symptoms in mice with overexpression of GLUT3 in cortical neurons. Specific readouts include molecular, behavioral, and electrophysiological techniques, of which our laboratories are very well-versed. This project is innovative as the role of glucose transport in HD has been underexplored, particularly during brain development. It is also highly significant as discovering new strategies to improve glucose transport into the brain during early development could be beneficial and hopefully prophylactic.