Deletion of glutamate dehydrogenase 1 (Glud1) in the central nervous system affects glutamate handling without altering synaptic transmission |
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Authors: | Mathias De Roo Vladimír Mlynárik Dorte M. Skytt Stefania Carobbio Kamilla Pajęcka Helle S. Waagepetersen Rolf Gruetter Dominique Muller Pierre Maechler |
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Affiliation: | 1. Department of Neuroscience, University of Geneva Medical Centre, , Geneva, Switzerland;2. Laboratory for Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne, , Lausanne, Switzerland;3. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, , Denmark;4. Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, , Geneva, Switzerland |
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Abstract: | Glutamate dehydrogenase (GDH), encoded by GLUD1, participates in the breakdown and synthesis of glutamate, the main excitatory neurotransmitter. In the CNS, besides its primary signaling function, glutamate is also at the crossroad of metabolic and neurotransmitter pathways. Importance of brain GDH was questioned here by generation of CNS‐specific GDH‐null mice (CnsGlud1?/?); which were viable, fertile and without apparent behavioral problems. GDH immunoreactivity as well as enzymatic activity were absent in Cns‐Glud1?/? brains. Immunohistochemical analyses on brain sections revealed that the pyramidal cells of control animals were positive for GDH, whereas the labeling was absent in hippocampal sections of Cns‐Glud1?/? mice. Electrophysiological recordings showed that deletion of GDH within the CNS did not alter synaptic transmission in standard conditions. Cns‐Glud1?/? mice exhibited deficient oxidative catabolism of glutamate in astrocytes, showing that GDH is required for Krebs cycle pathway. As revealed by NMR studies, brain glutamate levels remained unchanged, whereas glutamine levels were increased. This pattern was favored by up‐regulation of astrocyte‐type glutamate and glutamine transporters and of glutamine synthetase. Present data show that the lack of GDH in the CNS modifies the metabolic handling of glutamate without altering synaptic transmission. |
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Keywords: | astrocytes central nervous system Glud1 glutamate glutamate dehydrogenase |
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