Deletion of Neuronal GLT-1 in Mice Reveals Its Role in Synaptic Glutamate Homeostasis and Mitochondrial Function

• DOI: 10.1523/jneurosci.0894-18.2019
• Publication Date: 2019-03-29T22:25:12Z
• Authors: 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. Waagepet...
• Keywords: Synaptosome; Glutamic acid; Glutamate aspartate transporter; Synapsin I

The glutamate transporter GLT-1 is highly expressed in astrocytes but also neurons, primarily axon terminals. We generated a conditional neuronal KO using synapsin 1-Cre (synGLT-1 KO) to elucidate the metabolic functions of here focusing on cerebral cortex. Both synaptosomal uptake studies and electron microscopic immunocytochemistry demonstrated knockdown cortex synGLT-1 mice. Aspartate content was significantly reduced cortical extracts as well synaptosomes from compared with control littermates. ¹³C-Labeling tricarboxylic acid cycle intermediates originating metabolism [U-¹³C]-glutamate synaptosomes. decreased aspartate due diminished entry into cycle. Pyruvate recycling, pathway necessary for full oxidation, decreased. ATP production increased, despite unaltered oxygen consumption, isolated mitochondria KO. density terminals perisynaptic increased Intramitochondrial cristae mice suggesting mitochondrial efficiency, perhaps compensation access glutamate. SynGLT-1 exhibited an elevated consumption rate when stimulated veratridine, lower baseline presence glucose. neurons appears be required provide synaptic linked energy function. <b>SIGNIFICANCE STATEMENT</b> All transmitters need cleared extracellular space after release, transporters are used clear released excitatory synapses. major transporter, most astrocytes. Only 5%–10% function remains unknown. Here, we approach investigate significance expression neurons. found multiple abnormalities function, impairment utilization by These data suggest that may important maintaining biosynthetic activities mediated presynaptic mitochondria.