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

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-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.

Keywords

• Glut-1 deficiency mouse model
• Brain development
• Microcephaly
• Apoptosis
• Proliferation
• Astrogliosis