Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase
Wendy Xin,
Yevgeniya A. Mironova,
Hui Shen,
Rosa A.M. Marino,
Ari Waisman,
Wouter H. Lamers,
Dwight E. Bergles,
Antonello Bonci
Affiliations
Wendy Xin
Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD 21224, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Yevgeniya A. Mironova
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Hui Shen
Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD 21224, USA
Rosa A.M. Marino
Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD 21224, USA
Ari Waisman
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, 55128 Mainz, Germany
Wouter H. Lamers
Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, 1105 BK Amsterdam, the Netherlands
Dwight E. Bergles
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Antonello Bonci
Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD 21224, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Georgetown University Medical Center, School of Medicine, Washington, DC 20007, USA; Department of Psychiatry, University of Maryland, School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Summary: Glutamate has been implicated in a wide range of brain pathologies and is thought to be metabolized via the astrocyte-specific enzyme glutamine synthetase (GS). We show here that oligodendrocytes, the myelinating glia of the central nervous system, also express high levels of GS in caudal regions like the midbrain and the spinal cord. Selective removal of oligodendrocyte GS in mice led to reduced brain glutamate and glutamine levels and impaired glutamatergic synaptic transmission without disrupting myelination. Furthermore, animals lacking oligodendrocyte GS displayed deficits in cocaine-induced locomotor sensitization, a behavior that is dependent on glutamatergic signaling in the midbrain. Thus, oligodendrocytes support glutamatergic transmission through the actions of GS and may represent a therapeutic target for pathological conditions related to brain glutamate dysregulation. : Xin et al. show that mature oligodendrocytes, the myelinating cells of the brain, express the glutamine-synthesizing enzyme glutamine synthetase (GS). Oligodendrocyte-specific GS deletion does not impair myelination but disrupts neuronal glutamatergic transmission, thus demonstrating a myelin-independent role for oligodendrocytes in supporting glutamate signaling in the brain. Keywords: oligodendrocyte, glutamate, glutamine, transmission, midbrain, cocaine, glutamine synthetase, glia
