Murine Glut-1 transporter haploinsufficiency: postnatal deceleration of brain weight and reactive astrocytosis

Neurobiol Dis. 2009 Oct;36(1):60-9. doi: 10.1016/j.nbd.2009.06.014. Epub 2009 Jul 8.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Apoptosis / genetics
  • Astrocytes / metabolism
  • Astrocytes / pathology*
  • Body Weight / genetics
  • Brain / growth & development*
  • Brain / pathology*
  • Carbohydrate Metabolism, Inborn Errors / genetics
  • Carbohydrate Metabolism, Inborn Errors / pathology
  • Carrier Proteins / metabolism
  • Cell Proliferation
  • Cell Size
  • Cells, Cultured
  • Dendrites / pathology
  • Disease Models, Animal
  • Female
  • Fibroblasts / drug effects
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics*
  • Glial Fibrillary Acidic Protein / metabolism
  • Gliosis / genetics
  • Gliosis / metabolism
  • Gliosis / pathology*
  • Glucose Transporter Type 1 / deficiency*
  • Glucose Transporter Type 1 / genetics
  • Humans
  • Hypoglycemia / genetics
  • Hypoglycemia / pathology
  • Hypoglycemia / physiopathology
  • In Situ Nick-End Labeling / methods
  • Lithium Chloride / pharmacology
  • Magnetic Resonance Imaging / methods
  • Male
  • Mice
  • Mice, Knockout
  • Neurons / pathology
  • Organ Size / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Signal Transduction / genetics
  • Skin / cytology
  • TOR Serine-Threonine Kinases

Substances

  • Carrier Proteins
  • Glial Fibrillary Acidic Protein
  • Glucose Transporter Type 1
  • Phosphotransferases (Alcohol Group Acceptor)
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Lithium Chloride