Abstract
Glucose transporter type 1 (Glut-1) facilitates glucose flux across the blood-brain-barrier. In humans, Glut-1 deficiency causes acquired microcephaly, seizures and ataxia, which are recapitulated in our Glut-1 haploinsufficient mouse model. Postnatal brain weight deceleration and development of reactive astrogliosis were significant by P21 in Glut-1(+/-) mice. The brain weight differences remained constant after P21 whereas the reactive astrocytosis continued to increase and peaked at P90. Brain immunoblots showed increased phospho-mTOR and decreased phospho-GSK3-beta by P14. After fasting, the mature Glut-1(+/-) females showed a trend towards elevated phospho-GSK3-beta, a possible neuroprotective response. Lithium chloride treatment of human skin fibroblasts from control and Glut-1 DS patients produced a 45% increase in glucose uptake. Brain imaging of mature Glut-1(+/-) mice revealed a significantly decreased hippocampal volume. These subtle immunochemical changes reflect chronic nutrient deficiency during brain development and represent the experimental correlates to the human neurological phenotype associated with Glut-1 DS.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Age Factors
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Animals
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Animals, Newborn
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Apoptosis / genetics
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Astrocytes / metabolism
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Astrocytes / pathology*
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Body Weight / genetics
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Brain / growth & development*
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Brain / pathology*
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Carbohydrate Metabolism, Inborn Errors / genetics
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Carbohydrate Metabolism, Inborn Errors / pathology
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Carrier Proteins / metabolism
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Cell Proliferation
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Cell Size
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Cells, Cultured
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Dendrites / pathology
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Disease Models, Animal
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Female
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Fibroblasts / drug effects
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / genetics*
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Glial Fibrillary Acidic Protein / metabolism
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Gliosis / genetics
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Gliosis / metabolism
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Gliosis / pathology*
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Glucose Transporter Type 1 / deficiency*
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Glucose Transporter Type 1 / genetics
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Humans
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Hypoglycemia / genetics
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Hypoglycemia / pathology
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Hypoglycemia / physiopathology
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In Situ Nick-End Labeling / methods
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Lithium Chloride / pharmacology
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Magnetic Resonance Imaging / methods
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Male
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Mice
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Mice, Knockout
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Neurons / pathology
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Organ Size / genetics
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Signal Transduction / genetics
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Skin / cytology
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TOR Serine-Threonine Kinases
Substances
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Carrier Proteins
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Glial Fibrillary Acidic Protein
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Glucose Transporter Type 1
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Phosphotransferases (Alcohol Group Acceptor)
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MTOR protein, human
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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Lithium Chloride