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.