The goal of the proposed research plan is to understand -as quantitatively as possible- the dependence of brain excitability on brain energy metabolism by studying both the normal and a prototypic disease state. Glucose transporter type 1 (GLUT1) is the facilitative carrier responsible for all of the glucose transport across the blood brain barrier and into the astrocyte, and thus catalyzes the first step of normal brain energy metabolism. Both in man and mice, deficits in GLUT1 expression lead to epilepsy that can be ameliorated by increasing brain glucose supply or other alternative fuels (treatment with the ketogenic diet). In this study, we will use a mouse model of GLUT1 deficiency to gain information on how altered glucose flux into the brain causes epilepsy by analyzing neuronal excitability and neurotransmission through the use of whole cell patch clamp electrophysiology and nuclear magnetic resonance spectroscopy. The three specific aims are designed to 1) elucidate whether our disease model exhibits regional -rather than global- dysfunction by investigating intrinsic and driven cortical hyperexcitability, 2) quantify the contribution of neuronal versus glial excitatory and inhibitory neurotransmitters, and 3) investigate whether alternative fuels independent of glucose metabolism (such as those elevated in the ketogenic diet) can restore the excitability abnormalities seen in this model of epilepsy. Relevance Diseases of brain energy metabolism are almost always accompanied by epilepsy. It has been recognized for 50 years that both normal brain activity and epilepsy (defined as excess brain excitability) rely on brain energy supply, but their precise relationships (i.e., what fuel supplies are consumed by which specific brain cells, and how energy metabolism abnormalities often lead to epilepsy) are not known. The principal aim of this project is to understand and to measure the dependence of brain excitability on brain energy metabolism by studying both normal and disease states.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F01-S (20))
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Fureman, Brandy E
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University of Texas Sw Medical Center Dallas
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United States
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