Both excitatory and inhibitory synaptic transmission rely on the supply of glutamate. Glutamate is synthesized de novo from glucose and also recycled through the glutamate-glutamine cycle between neurons and astrocytes. GABA used for synaptic transmission is also dependent on neuronal-glial cycling as GABA is synthesized from glutamate which can enter interneurons either via uptake or through glutamine. The main goal of this proposal is to test the broad hypothesis that cellular excitability is intimately tied to the status of glutamate-glutamine-GABA cycling and specifically that GABAergic transmission is more sensitive than excitatory transmission to disruption in cycling during periods of sustained neuronal activity because of the added energy-dependent steps needed for the synthesis of GABA.
In Specific Aim 1 we will interrupt cycling a several different levels including blockade of the synthetic enzymes of glutamine, glutamate and GABA as well as by blocking glutamine uptake. The effect of these metabolic inhibitors on synaptic inhibition will be examined physiologically.
In Specific Aim 2, we will use mass spectometry to measure the changes in the levels of glutamate, glutamine and GABA induced by alterations in neurotransmitter cycling in both the tissue and in the bathing medium to address the time-dependent changes in transmitter levels.
In Specific Aim 3 will use 13C isomer spectroscopy to assess the effect of those compounds that cross the blood brain barrier (the GS inhibitor methionine sulfoximine and the glutamine transporter MeAIB) on glutamate-glutamine-GABA cycling in control animals. These experiments should provide important data on the regulation of normal synaptic transmission as well as an understanding of the pathology of a number of neurological disorders where changes in neural energetics have been seen including epilepsy, ALS and Huntington's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS045792-01A1
Application #
6774428
Study Section
Special Emphasis Panel (ZRG1-CNNT (01))
Program Officer
Jacobs, Margaret
Project Start
2004-04-01
Project End
2007-01-31
Budget Start
2004-04-01
Budget End
2005-01-31
Support Year
1
Fiscal Year
2004
Total Cost
$264,666
Indirect Cost
Name
Yale University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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