Gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian cortex. Extensive work in animals has shown that changes in GABA metabolism plays an important role in the original and spread of seizure activity. This project will center on the enzymatic control of flux through key enzymes of GABA synthesis (glutamic acid decarboxylase, GAD) and degradation (GABA-transaminase) in the cortex of rats treated with vigabatrin (gamma-vinyl-GABA), a highly specific GABA-transaminase inhibitor and one of the most promising new anti-epileptic drugs under clinical development. Our general hypothesis is that changes in the rate of cortical GABA synthesis following a prolonged increase in GABA concentration in vivo can be interpreted quantitatively in terms of GABA-induced changes in the isoform composition and activity of GAD. Also that inhibition of GABA metabolism interrupts carbon and nitrogen cycling between neurons and glia, altering glutamate and glutamine metabolism in vivo. We propose four specific aims: 1) Investigate the relationship between the in vivo rate of cortical GABA synthesis, GABA concentration and GAD activity (i.e., total GAD and major GAD isoforms) after acute and prolonged GABA elevation, 2) Determine the changes in the in vivo rate of cortical GABA synthesis and GAD activity during seizures and 3) in response to stimulation of the somatosensory cortex. 4) Determine the relationship between the changes in the rate of turnover of GABA measured in brain tissue in vivo and GABA in the extracellular fluid during acute and chronic GABA-transaminase inhibition. Using in vivo NMR Spectroscopy, Magnetic Resonance Imaging, in vivo microdialysis, immunologic and enzymatic assays in vitro, we will examine the role of GABa and other modulators in the control of GABA synthesis and the regulation of GABA levels in vivo. The uniqueness of this project derives from 1) the approach of combining in vivo and in vitro techniques, 2) the track record of the investigators in addressing questions using NMR, and 3) the fact that this project complements ongoing clinical investigations of GABA and glutamate metabolism in epilepsy and the effects of antiepileptic medications on the metabolic pathways of the human brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034813-04
Application #
2892034
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Jacobs, Margaret
Project Start
1996-07-22
Project End
2001-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
082359691
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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