The experiments in Part I of this proposal will test the hypothesis that alterations in the structure and regulation of the GABA synthetic enzyme, glutamate decarboxylase (GAD), or of GABAA receptor polypeptides underlie the seizure disorders in animal models of epilepsy. Part I encompasses two specific aims: (1) to determine whether one of the genes encoding GAD or GABA receptor polypeptides is altered in one of the existing genetic mouse models of epilepsy, and (2) to determine whether the expression of GAD or GABA receptor genes is altered in several genetic and experimental models or epilepsy. The experiments proposed in Part II of this proposal will attempt to program the altered expression of GAD and GABA receptor polypeptides in cell lines and in transgenic mice. Part II encompasses three specific aims: (3) to program high level expression of GAD in subclones of existing cell lines, (4) to determine the mechanism of GABA release in these engineered cell lines, and (5) to determine whether seizure susceptibility is altered in transgenic mice with altered expression of GAD or GABA receptors. Direct injection of GABA agonists into the brain in some cases prevents seizure propagation and cell death. A long term goal of the experiments proposed in specific aims #3 and 4 is the production of engineered cell lines that could provide a continuing and regulatable source of GABA. Such """"""""designer neurons"""""""" may be ultimately useful in transplantation therapies for intractable seizures or for such neurodegenerative diseases as Huntington's disease. If we succeed in producing cells that release GABA, either constitutively or in response to depolarization, we will then, in collaboration with other investigators, address the problems of transplantation into experimental animals and testing for seizure suppression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022256-05
Application #
3404466
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1985-04-01
Project End
1993-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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