Role of Glutamate Dehydrogenase in Carbohydrate, Amino Acid and Energy Metabolism of Neurons

• Applicant: Dr. Michaela C. Hohnholt
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260140329

Brain neurons are controlling all functions of the body. Although the importance of neuronal health is generally acknowledged, surprisingly little is known about neuronal metabolism. Glutamate dehydrogenase (GDH) is a mitochondrial enzyme that links carbohydrate, amino acid and energy metabolism of cells. The proposed research project will investigate the role of the central enzyme GDH in neuronal metabolism. A mouse with a central nervous system (CNS) specific deletion of the GDH gene Glud1 (CNS-Glud1-/-mice) has been generated recently and the ablation of GDH in the brain of these mice has been confirmed. In vitro cerebellar granule neuron cultures, neuron-astrocyte co-cultures and brain slices from CNS-Glud1-/-mice will be used as model systems. The comparison of data obtained on cell cultures or brain slices from CNS-Glud1-/-mice with control mice will provide information of the role of GDH in neuronal metabolism. Analysis of the metabolism by metabolic mapping employing 13C- and 15N-labeled substrates (e.g. glucose or glutamate) by mass spectrometry and nuclear magnetic resonance spectroscopy will reveal a detailed picture about the role of GDH in neurons. Analysis of the metabolism of neurons in neuron-astrocyte co-cultures and brain slices from CNS-Glud1-/-mice will clarify the role of the neuronal GDH in the metabolic interactions of neurons and astrocytes. Moreover, the importance of GDH for both the glycolytic and mitochondrial neuronal energy production and the neuronal content of the glutamate-containing antioxidant glutathione will be studied. Also, investigations of release and reuptake of the neurotransmitter glutamate will reveal valuable insights into the role of GDH in neurotransmission between neurons. In summary, this project will supply fundamental informations of the role of GDH in neuronal energy metabolism, which will also be essential for further investigations of the contribution of GDH-malfunction in neurological diseases and diseases affecting the brain.

• DFG Programme: Research Fellowships
• International Connection: Denmark
• Host: Professorin Dr. Helle S. Waagepetersen