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首选的能量底物。在静息状态下，葡萄糖被吸收成 由葡萄糖转运蛋白3(GLUT3)激活的神经元。然而，在亨廷顿病(HD)中，一种遗传的，致命的， 亨廷顿基因突变引起的神经退行性疾病，其特征是异常 运动以及认知和精神症状、脑能量代谢和GLUT3表达 显著减少了。我们小组和其他人最近的研究也强调了 HD中的神经发育成分。特别是，我们报告了大脑的结构异常 HD模型小鼠的大脑皮质，这让人想起皮质发育的畸形。我们假设 在HD患者中，GLUT3缺陷导致大脑发育异常，导致皮质过度兴奋和进行性 出现症状。目前的建议是为了在幼年和成年小鼠身上检查 HD模型，GLUT3在皮质发育中的作用，如果被证实有缺陷，则逆转这一缺陷，并 防止表型的发展。有两个具体目标：目标1将主要审查GLUT3 在发育中的HD小鼠中的表达，从胚胎到成体阶段。目标2将使用遗传策略来探索 GLUT3低表达或高表达如何影响疾病进展。我们已经产生了 并描述了缺乏GLUT3的小鼠模型，为了这个项目，我们将创建一个新的GLUT3系列 过量表达的小鼠，这将与HD小鼠杂交。我们希望看到HD症状的改善 在皮质神经元GLUT3过度表达的小鼠中。具体读数包括分子、行为和 电生理技术，我们的实验室对此非常熟悉。这个项目是创新的，因为 葡萄糖转运在HD中的作用一直没有得到充分的研究，特别是在大脑发育过程中。它也高度地 重要的是发现了在发育早期改善葡萄糖进入大脑的新策略 可能是有益的，希望是预防的。

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.