Decreasing the expression of the neuronal glutamate transporter, EAAC1, causes epilepsy in adult rats. Recent metabolic studies indicate that this seizure activity may result from a reduced synthesis of GABA, implicating the involvement of EAAC1 in normal GABA metabolism. These results offer new insights about the cellular mechanisms responsible for maintaining the transmitter pool of GABA. We propose to investigate the relationship between glutamate uptake by EAAC1 and epilepsy, by manipulating EAAC1 activity in vivo, and examining the effect that this has on seizures, glutamate uptake, GABA synthesis, and synaptic inhibition. Recently, a novel protein was identified and characterized that is an endogenous negative regulator of EAAC1. This protein, GTRAP3-18 (Glutamate Transporter Associated Protein 3-18), may play a critical role in the regulation of GABA metabolism through its effect on glutamate uptake mediated by EAAC1. The overall goals of this project are to determine, (1) if decreasing EAAC1 expression decreases GABA synthesis and causes epilepsy in adult rat, (2) if interfering with EAAC1 metabolism directly or indirectly through GTRAP3-18 disrupts the synthesis of GABA. These studies of EAAC1 involvement in GABA metabolism may lead to new insights into the causes of epilepsies, and help to develop novel therapeutic approaches for treating a variety of seizure disorders. Significance: The studies proposed in this grant seek to define the relationship between the glutamate transporter EAAC1, GABA metabolism, and epilepsy in the adult brain. We plan to test whether an increase in the level of GTRAP3-18, a negative regulator of EAAC1 activity, causes epilepsy, and alternatively, whether decreasing GTRAP3-18 expression decreases seizure susceptibility. Our hope is that these studies of the links between glutamate uptake by EAAC1 and the efficacy of GABAergic transmission, may help to identify novel approaches for treating epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS042357-02
Application #
6640148
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Fureman, Brandy E
Project Start
2002-07-01
Project End
2004-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$239,940
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218