For the last 10-15 years our laboratory has had a major role in the development and use of new spectroscopy and imaging techniques in vivo to study the regulation of pathways of brain glucose metabolism. Over the last 4 years of this grant we reported a number of important findings which indicate that release of glutamate and GABA from neurons and their cycling between neurons and glia has a major influence on brain energy metabolism and that the isoforms of a key enzyme of GABA synthesis, glutamic acid decarboxylase (GAD) mediate different proportions of total GABA synthesis. Our central hypothesis is that specific GAD isoforms and supply routes of glutamate carbon play key roles in regulating GABA synthesis and GABA neurotransmitter cycling. We propose the following specific aims: 1a) Determine the relationship between the rates of GABA synthesis, GABA neurotrasmitter cycling, and glutamate/glutamine cycle over a wide range of cortical metabolic activity. 1b) Assess the role of cofactor interaction and phosphorylation of the GAD isoforms in the regulation of GABA synthesis and GABA/glutamine cycling flux. 2) Investigate the role of GAD isoforms in regulation of GABA cycling flux through the two glutamate precursor pathways using GABA-transaminase inhibition and GABA elevation to selectively alter GAD isoform composition. 3) Quantitate the key metabolic pathway fluxes that supply glutamate precursors for GABA synthesis and GABA/glutamine cycling. 4) Determine the relationship between vesicular and non-vesicular GABA, precursor glutamate pathways, and GAD isoforms using diffusion-sensitized MRS in vivo. Using Magnetic Resonance spectroscopy (MRS) and 13C-labeled isotopes in vivo, and enzymatic assays in vitro with pharmacological and molecular biological interventions, we will examine the role of GAD isoforms and glutamate precursors in GABA synthesis and GABA neurotransmitter cycling The uniqueness of this project derives from i) the combination of the these techniques, ii) the track record of the investigator in addressing such questions using MRS, and iii) it complements ongoing clinical investigations of GABA and glutamate metabolism in epilepsy and neuropsychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034813-09
Application #
6780929
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Fureman, Brandy E
Project Start
1996-07-22
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2006-07-31
Support Year
9
Fiscal Year
2004
Total Cost
$390,025
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Patel, Anant B; Lai, James C K; Chowdhury, Golam I M et al. (2017) Comparison of Glutamate Turnover in Nerve Terminals and Brain Tissue During [1,6-13C2]Glucose Metabolism in Anesthetized Rats. Neurochem Res 42:173-190
Patel, Anant B; de Graaf, Robin A; Rothman, Douglas L et al. (2015) Effects of ?-Aminobutyric acid transporter 1 inhibition by tiagabine on brain glutamate and ?-Aminobutyric acid metabolism in the anesthetized rat In vivo. J Neurosci Res 93:1101-8
Malthankar-Phatak, Gauri H; Patel, Anant B; Xia, Ying et al. (2008) Effects of continuous hypoxia on energy metabolism in cultured cerebro-cortical neurons. Brain Res 1229:147-54
Chowdhury, Golam M I; Patel, Anant B; Mason, Graeme F et al. (2007) Glutamatergic and GABAergic neurotransmitter cycling and energy metabolism in rat cerebral cortex during postnatal development. J Cereb Blood Flow Metab 27:1895-907
Chowdhury, G M I; Gupta, M; Gibson, K M et al. (2007) Altered cerebral glucose and acetate metabolism in succinic semialdehyde dehydrogenase-deficient mice: evidence for glial dysfunction and reduced glutamate/glutamine cycling. J Neurochem 103:2077-91
Patel, Anant B; de Graaf, Robin A; Martin, David L et al. (2006) Evidence that GAD65 mediates increased GABA synthesis during intense neuronal activity in vivo. J Neurochem 97:385-96
Kida, Ikuhiro; Smith, Arien J; Blumenfeld, Hal et al. (2006) Lamotrigine suppresses neurophysiological responses to somatosensory stimulation in the rodent. Neuroimage 29:216-24
de Graaf, Robin A; Patel, Anant B; Rothman, Douglas L et al. (2006) Acute regulation of steady-state GABA levels following GABA-transaminase inhibition in rat cerebral cortex. Neurochem Int 48:508-14
Malthankar-Phatak, Gauri H; de Lanerolle, Nihal; Eid, Tore et al. (2006) Differential glutamate dehydrogenase (GDH) activity profile in patients with temporal lobe epilepsy. Epilepsia 47:1292-9
Hyder, Fahmeed; Patel, Anant B; Gjedde, Albert et al. (2006) Neuronal-glial glucose oxidation and glutamatergic-GABAergic function. J Cereb Blood Flow Metab 26:865-77

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