Deletion of neuronal GLT-1 in mice reveals its role in synaptic glutamate homeostasis and mitochondrial function

Laura F. McNair, Jens V. Andersen, Blanca I. Aldana, Michaela C. Hohnholt, Jakob D. Nissen, Yan Sun, Kathryn D. Fischer, Ursula Sonnewald, Nils Nyberg, Sophie C. Webster, Kush Kapur, Theresa S. Rimmele, Ilaria Barone, Hannah Hawks-Mayer, Jonathan O. Lipton, Nathaniel W. Hodgson, Takao K. Hensch, Chiye J. Aoki, Paul A. Rosenberg, Helle S. Waagepetersen

Research output: Contribution to journalArticlepeer-review


The glutamate transporter GLT-1 is highly expressed in astrocytes but also in neurons, primarily in axon terminals. We generated a conditional neuronal GLT-1KOusing synapsin 1-Cre (synGLT-1 KO) to elucidate the metabolic functions of GLT-1 expressed in neurons, here focusing on the cerebral cortex. Both synaptosomal uptake studies and electron microscopic immunocytochemistry demonstrated knockdown of GLT-1 in the cerebral cortex in the synGLT-1 KO mice. Aspartate content was significantly reduced in cerebral cortical extracts as well as synaptosomes from cerebral cortex of synGLT-1 KO compared with control littermates. 13C-Labeling of tricarboxylic acid cycle intermediates originating from metabolism of [U-13C]-glutamate was significantly reduced in synGLT-1KOsynaptosomes. The decreased aspartate content was due to diminished entry of glutamate into the tricarboxylic acid cycle. Pyruvate recycling, a pathway necessary for full glutamate oxidation, was also decreased. ATP production was significantly increased, despite unaltered oxygen consumption, in isolated mitochondria from the synGLT-1 KO. The density of mitochondria in axon terminals and perisynaptic astrocytes was increased in the synGLT-1 KO. Intramitochondrial cristae density of synGLT-1 KO mice was increased, suggesting increased mitochondrial efficiency, perhaps in compensation for reduced access to glutamate. SynGLT-1KOsynaptosomes exhibited an elevated oxygen consumption rate when stimulated with veratridine, despite a lower baseline oxygen consumption rate in the presence of glucose. GLT-1 expressed in neurons appears to be required to provide glutamate to synaptic mitochondria and is linked to neuronal energy metabolism and mitochondrial function.

Original languageEnglish (US)
Pages (from-to)4847-4863
Number of pages17
JournalJournal of Neuroscience
Issue number25
StatePublished - Jun 19 2019


  • Anaplerosis
  • Aspartate
  • Bioenergetics
  • Huntington’s
  • Neurodegeneration
  • TCA cycle

ASJC Scopus subject areas

  • General Neuroscience


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