Glutamate uptake is the primary mechanism for its removal from the synapse. Reversal of the glutamate transporter is believed to be responsible for the excess glutamate leading to excitotoxicity found in ischemia (Szakowski and Atwell, 1994, Choi, 1992). Significant changes in glutamate uptake have been observed in several models of experimental epilepsy (Cordero et al., 1994, Ortiz et al., 1995). Working Hypotheses: (1) Glutamate uptake plays a crucial role in glutamate uptake; (2) Glutamate uptake is regulated by cellular messengers such as NO, IP3, (perhaps thru mGLURs); and (3) Perturbations in glutamate uptake or its regulation may result in altered seizure susceptibility;
The SPECIFIC AIMS of this proposal are: (1) Establish the time course and reversibility of the changes in glutamate uptake brought about by interfering with glutamate transmission in normal mouse brain synaptosomes; (2) To identify cellular signals, such as NO or IP3 that may regulate changes in glutamate uptake in normal mouse brain synaptosomes or cultured neural cells (ie. astrocytes). Once these messengers are identified, determine whether these signals are altered i experimental epilepsy; (3) Determine if interference with glutamate uptake regulation alters susceptibility to pentylenetetrazole or kainic acid seizures in adult normal mice. Determine whether the acquisition of audiogenic seizures, either genetic or induced is modified by interfering with the regulation of glutamate uptake; (4) Provide students with training in the neurochemistry and neuropharmacology of experimental epilepsy. A comparison of the results of genetic vs. induced epilepsies should determine to what extent seizure susceptibility (genetic vs. acquired) can be modified by interfering with the regulation of glutamate uptake and could represent a potential therapeutic approach.

Project Start
1998-08-01
Project End
1999-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
14
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Puerto Rico Med Sciences
Department
Type
DUNS #
City
San Juan
State
PR
Country
United States
Zip Code
00936
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