Project Summary Relative to its size, the human brain consumes a disproportionately large quantity of the body’s total energy needs. This energy, delivered mainly in the form of glucose, must be readily available and supplied to the brain on-demand. Failure to do so has dire consequences for the organism, resulting in a state of neuroglycopenia and, in severe instances, coma and death. While the overt consequence of chronic neuroglycopenia – cognitive dysfunction – is easily recognized and well-established, its cellular and molecular correlates are yet to be fully defined. One way of gaining an understanding of the mechanistic details underlying brain energy deprivation is through the study of genetically determined brain energy failure syndromes. Glucose Transporter-1 deficiency syndrome (Glut1 DS) is the quintessential example. Caused by low levels of the principal glucose transporter (Glut1) of the brain, the disease strikes mainly in infancy or early childhood and is characterized by severe epileptic seizures, low brain glucose, cognitive dysfunction and a complex movement disorder that worsens with age. Yet, there is no truly effective treatment that addresses the root cause of Glut1 DS, and little understanding of the molecular and cellular mechanisms that account for the phenotypic presentation of the disease. We wish to address these deficiencies, and propose to do so through the development of novel “humanized” Glut1 DS model mice harboring the entire human Glut1 locus – the objective of this proposal. Preliminary work has already resulted in several lines of these mice. During the project period, we will thoroughly characterize the mice, employing a battery of well-established molecular, cellular and behavioral assays that we have optimized in the lab. A successful outcome to the project will result in an invaluable tool to probe basic mechanisms underlying not just Glut1 DS but also the larger family of brain energy failure syndromes. Moreover, the mice are expected to prove useful in Glut1 DS therapy development; raising Glut1 levels is an intuitively appealing therapeutic strategy and agents that have the potential to do so are best tested in an in vivo model endowed with the human Glut1 gene.