Neurobiology of Disease 2009-01-01

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

Paivi M. Ullner, Alessia Di Nardo, James E. Goldman, Scott Schobel, Hong Yang, Kristin Engelstad, Dong Wang, Mustafa Sahin, Darryl C. De Vivo, Paivi M. Ullner, Alessia Di Nardo, James E. Goldman, Scott Schobel, Hong Yang, Kristin Engelstad, Dong Wang, Mustafa Sahin, Darryl C. De Vivo

文献索引：Neurobiol. Dis. 36 , 60-9, (2009)

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摘要

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-β by P14. After fasting, the mature Glut-1 +/− females showed a trend towards elevated phospho-GSK3-β, 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.