Murine Glut-1 transporter haploinsufficiency: postnatal deceleration of brain weight and reactive astrocytosis.
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.
Ullner
Paivi M
PM
Department of Neurology, Colleen Giblin Laboratories for Pediatric Neurology Research, Columbia University, New York, NY, USA.
Di Nardo
Alessia
A
Goldman
James E
JE
Schobel
Scott
S
Yang
Hong
H
Engelstad
Kristin
K
Wang
Dong
D
Sahin
Mustafa
M
De Vivo
Darryl C
DC
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000254:growth & development* / Q000473:pathology*; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation; D048429:Cell Size; D002478:Cells, Cultured; D003712:Dendrites / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051272:Glucose Transporter Type 1 / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D020287:In Situ Nick-End Labeling / Q000379:methods; D018021:Lithium Chloride / Q000494:pharmacology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology; D009929:Organ Size / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D012867:Skin / Q000166:cytology; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; D005904:Glial Fibrillary Acidic Protein; D051272:Glucose Transporter Type 1; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D018021:Lithium Chloride