Glutamine synthetase deficiency in murine astrocytes results in neonatal death

Y. He, T.B. Hakvoort, J.L. Vermeulen, W.T. Labruyere, D.R. de Waart, W.S. van der Hel, J.M. Ruijter, H.B. Uylings, W.H. Lamers

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Glutamine synthetase (GS) is a key enzyme in the "glutamine-glutamate cycle" between astrocytes and neurons, but its function in vivo was thus far tested only pharmacologically. Crossing GS(fl/lacZ) or GS(fl/fl) mice with hGFAP-Cre mice resulted in prenatal excision of the GS(fl) allele in astrocytes. "GS-KO/A" mice were born without malformations, did not suffer from seizures, had a suckling reflex, and did drink immediately after birth, but then gradually failed to feed and died on postnatal day 3. Artificial feeding relieved hypoglycemia and prolonged life, identifying starvation as the immediate cause of death. Neuronal morphology and brain energy levels did not differ from controls. Within control brains, amino acid concentrations varied in a coordinate way by postnatal day 2, implying an integrated metabolic network had developed. GS deficiency caused a 14-fold decline in cortical glutamine and a sevenfold decline in cortical alanine concentration, but the rising glutamate levels were unaffected and glycine was twofold increased. Only these amino acids were uncoupled from the metabolic network. Cortical ammonia levels increased only 1.6-fold, probably reflecting reduced glutaminolysis in neurons and detoxification of ammonia to glycine. These findings identify the dramatic decrease in (cortical) glutamine concentration as the primary cause of brain dysfunction in GS-KO/A mice. The temporal dissociation between GS(fl) elimination and death, and the reciprocal changes in the cortical concentration of glutamine and alanine in GS-deficient and control neonates indicate that the phenotype of GS deficiency in the brain emerges coincidentally with the neonatal activation of the glutamine-glutamate and the associated alanine-lactate cycles. (c) 2010 Wiley-Liss, Inc.
Original languageEnglish
Pages (from-to)741-754
Number of pages14
JournalGlia
Volume58
Issue number6
DOIs
Publication statusPublished - 15 Apr 2010

Keywords

  • mouse
  • conditional gene inactivation
  • brain
  • astrocytes
  • glutamine
  • glutamate
  • alanine
  • glycine
  • CENTRAL-NERVOUS-SYSTEM
  • FIBRILLARY ACIDIC PROTEIN
  • METABOLIC COMPARTMENTATION
  • NMDA RECEPTORS
  • HEPATIC-ENCEPHALOPATHY
  • AMINO-ACIDS
  • RAT-BRAIN
  • AMMONIA
  • GENE
  • EXPRESSION

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