Conditional Knockout of GLT-1 in Neurons Leads to Alterations in Aspartate Homeostasis and Synaptic Mitochondrial Metabolism in Striatum and Hippocampus

Laura F. McNair, Jens V. Andersen, Jakob D. Nissen, Yan Sun, Kathryn D. Fischer, Nathaniel W. Hodgson, Muzi Du, Chiye J. Aoki, Helle S. Waagepetersen, Paul A. Rosenberg, Blanca I. Aldana

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Abstract

Expression of the glutamate transporter GLT-1 in neurons has been shown to be important for synaptic mitochondrial function in the cerebral cortex. Here we determined whether neuronal GLT-1 plays a similar role in the hippocampus and striatum, using conditional GLT-1 knockout mice in which GLT-1 was inactivated in neurons by expression of synapsin-Cre (synGLT-1 KO). Ex vivo 13C-labelling using [1,2-13C]acetate, representing astrocytic metabolism, yielded increased [4,5-13C]glutamate levels, suggesting increased astrocyte-neuron glutamine transfer, in the striatum but not in the hippocampus of the synGLT-1 KO. Moreover, aspartate concentrations were reduced − 38% compared to controls in the hippocampus and the striatum of the synGLT-1 KO. Mitochondria isolated from the hippocampus of synGLT-1 KO mice exhibited a lower oxygen consumption rate in the presence of oligomycin A, indicative of a decreased proton leak across the mitochondrial membrane, whereas the ATP production rate was unchanged. Electron microscopy revealed reduced mitochondrial inter-cristae distance within excitatory synaptic terminals in the hippocampus and striatum of the synGLT-1 KO. Finally, dilution of 13C-labelling originating from [U-13C]glucose, caused by metabolism of unlabelled glutamate, was reduced in hippocampal synGLT-1 KO synaptosomes, suggesting that neuronal GLT-1 provides glutamate for synaptic tricarboxylic acid cycle metabolism. Collectively, these data demonstrate an important role of neuronal expression of GLT-1 in synaptic mitochondrial metabolism in the forebrain.

Original languageEnglish (US)
JournalNeurochemical Research
DOIs
StateAccepted/In press - Jan 1 2020

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Keywords

  • Brain energy metabolism
  • Forebrain
  • Glutamate
  • Glutamine
  • TCA cycle

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

McNair, L. F., Andersen, J. V., Nissen, J. D., Sun, Y., Fischer, K. D., Hodgson, N. W., Du, M., Aoki, C. J., Waagepetersen, H. S., Rosenberg, P. A., & Aldana, B. I. (Accepted/In press). Conditional Knockout of GLT-1 in Neurons Leads to Alterations in Aspartate Homeostasis and Synaptic Mitochondrial Metabolism in Striatum and Hippocampus. Neurochemical Research. https://doi.org/10.1007/s11064-020-03000-7