Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the human cortex. Extensive studies in animals have shown that changes in GABA physiology have an important role in the origin and spread of seizure activity. The studies proposed here will use unique, non-invasive nuclear magnetic resonance spectroscopy (NMRS) to investigate GABA levels in the brain s of children with generalized, cryptogenic epilepsies who have normal anatomical neuroimaging. Recent advances in nuclear magnetic resonance spectroscopy developed in our laboratory have permitted the first non-invasive measurement of cerebral glutamate and GABA in humans. Studies of GABA synthesis and catabolism in human cortex using both proton and carbon NMRS methods will further understanding of this important neurotransmitter's role in generalized epilepsy. Our general hypothesis is that intrinsic defects of GABA physiology and metabolism result in epilepsy in these children with cryptogenic generalized epilepsy. Subjects will be identified by alterations in steady-state GABA levels as measured by proton NMRS and by both the biochemical and clinical responses to agents known to alter GABA metabolism. We will then use 13C NMRS to measure the turnover rates of GABA and precursor amino acid pools to investigate the mechanisms by which the observed alterations in GABA homeostasis occur. Studies of GABA synthesis and catabolism in human cortex using both proton and carbon NMRS methods will further understanding of this important neurotransmitter's role in generalized epilepsies in childhood. The information obtained from proposed studies will advance our understanding and ultimately improve the clinical care of children and adults with epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038175-03
Application #
6330570
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Fureman, Brandy E
Project Start
1999-01-04
Project End
2002-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
3
Fiscal Year
2001
Total Cost
$284,518
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Shen, Ke-Zhong; Johnson, Steven W (2008) Complex EPSCs evoked in substantia nigra reticulata neurons are disrupted by repetitive stimulation of the subthalamic nucleus. Synapse 62:237-42
Shen, K-Z; Johnson, S W (2008) 5-HT inhibits synaptic transmission in rat subthalamic nucleus neurons in vitro. Neuroscience 151:1029-33
Shen, K-Z; Kozell, L B; Johnson, S W (2007) Multiple conductances are modulated by 5-HT receptor subtypes in rat subthalamic nucleus neurons. Neuroscience 148:996-1003
Shen, Ke-Zhong; Johnson, Steven W (2006) Subthalamic stimulation evokes complex EPSCs in the rat substantia nigra pars reticulata in vitro. J Physiol 573:697-709
Pearl, Phillip L; Capp, Philip K; Novotny, Edward J et al. (2005) Inherited disorders of neurotransmitters in children and adults. Clin Biochem 38:1051-8
Shen, Ke-Zhong; Johnson, Steven W (2005) Dopamine depletion alters responses to glutamate and GABA in the rat subthalamic nucleus. Neuroreport 16:171-4
Shen, Ke-Zhong; Zhu, Zi-Tao; Munhall, Adam et al. (2003) Dopamine receptor supersensitivity in rat subthalamus after 6-hydroxydopamine lesions. Eur J Neurosci 18:2967-74
Novotny Jr, Edward J; Fulbright, Robert K; Pearl, Phillip L et al. (2003) Magnetic resonance spectroscopy of neurotransmitters in human brain. Ann Neurol 54 Suppl 6:S25-31
Shen, Ke-Zhong; Johnson, Steven W (2003) Group II metabotropic glutamate receptor modulation of excitatory transmission in rat subthalamic nucleus. J Physiol 553:489-96
Shen, Ke-Zhong; Zhu, Zi-Tao; Munhall, Adam et al. (2003) Synaptic plasticity in rat subthalamic nucleus induced by high-frequency stimulation. Synapse 50:314-9

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