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

神经元葡萄糖转运不足是亨廷顿病小鼠模型皮质过度兴奋的基础

基本信息

批准号：
10452907
负责人：
Carlos T Cepeda
金额：
$ 19.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452907
关键词：
Adolescent Adult Affect Applications Grants Behavioral Biological Blood - brain barrier anatomy Blood Circulation Brain CAG repeat Cell physiology Cells Cerebral cortex Corpus striatum structure Cortical Malformation Data Defect Development Disease Disease Progression Disease model Dyskinetic syndrome Electrophysiology (science)Embryo Energy Metabolism Etiology Evolution Gene Deletion Generations Genes Genetic Glucose Glucose Transporter Goals Huntington Disease Huntington gene Investigation Joints Juvenile-Onset Huntington Disease Laboratories Lead Lesion Mediating Modeling Modification Molecular Molecular Genetics Mus Mutation Nerve Degeneration Neurobehavioral Manifestations Neurodegenerative Disorders Neurons Pathologic Pathology Patients Pharmacology Phenotype Physiological Proteins Recording of previous events Reporting Rest Role SLC2A1 gene Schizophrenia Seizures Starvation Structural defect Symptoms Techniques Testing Transgenic Mice Up-Regulation autism spectrum disorder brain abnormalities brain cell design disease phenotype experimental study genetic approach genetic technology glucose metabolism glucose transport improved innovation lipid metabolism mouse model mutant optogenetics overexpression postnatal development prevent prophylactic protein expression psychiatric symptom symptomatology targeted treatment

项目摘要

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.

抽象的葡萄糖是大脑中的主要和首选能量底物。在静止条件下，葡萄糖被吸收到葡萄糖转运蛋白3（GLUT3）的神经元。但是，在亨廷顿氏病（HD）中，一种遗传，致命，神经退行性疾病是由亨廷汀基因突变引起的，并以异常为特征运动，认知和精神病症状，大脑能量代谢和GLUT3表达大大减少。我们小组和其他人的最新研究也强调了 HD中的神经发育成分。特别是，我们报道了脑的结构异常 HD模型小鼠的皮质，使人想起皮质发育的畸形。我们假设这一点在HD中，GLUT3定义导致脑发育异常，导致皮质过度兴奋和进行性症状的出现。本提案旨在检查少年和成人鼠标高清模型，GLUT3在皮质发育中的作用，如果证明不足，可以扭转这种缺陷和防止表型的发展。有两个具体的目标：AIM 1将检查，主要，Glut3 从胚胎到成年阶段的发展中HD小鼠的表达。 AIM 2将使用遗传策略探索 GLUT3的不足或过表达如何影响疾病进展的发展。我们已经生成了并表征了GLUT3缺乏鼠标的模型，对于此项目，我们将创建一条新的GLUT3行过表达的小鼠将与HD小鼠交叉。我们希望看到高清症状的改善在皮质神经元中GLUT3过表达的小鼠中。特定的读数包括分子，行为和电生理技术，我们的实验室非常精通。这个项目是创新的葡萄糖转运在HD中的作用尚未逐渐倍增，尤其是在大脑发育过程中。也很高重要的是发现了早期开发过程中改善葡萄糖转运到大脑的新策略可能是有益的，希望是预防性的。