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主要且优选的能量底物，在静息状态下，葡萄糖被吸收。然而，在亨廷顿病 (HD) 中，葡萄糖转运蛋白 3 (GLUT3) 是一种遗传性、致命性的疾病。由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、认知和精神症状、脑能量代谢和 GLUT3 表达我们小组和其他人最近的研究也显着减少了。特别是，我们报道了 HD 中的神经发育成分。 HD模型小鼠的皮质，这让人想起皮质发育畸形。在 HD 中，GLUT3 缺陷会导致大脑发育异常，从而导致皮质过度兴奋和进行性进展本提案旨在检查幼年和成年发病的小鼠。 HD 模型，GLUT3 在皮质发育中的作用，如果被证明存在缺陷，则扭转这种缺陷，阻止表型的发展有两个具体目标：目标 1 将主要检查 GLUT3。 Aim 2 将使用遗传策略来探索 HD 小鼠从胚胎到成年阶段的表达。我们已经研究了 GLUT3 的表达不足或过度表达如何影响疾病进展。并表征了 GLUT3 缺陷小鼠模型，对于这个项目，我们将创建一个新的 GLUT3 系列过度表达的小鼠将与 HD 小鼠杂交，我们期望看到 HD 症状的改善。在皮质神经元中过度表达 GLUT3 的小鼠中，具体读数包括分子、行为和神经元。我们的实验室非常精通电生理学技术，该项目具有创新性。葡萄糖转运在 HD 中的作用尚未得到充分研究，特别是在大脑发育过程中。重要的是发现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，并有望起到预防作用。