Abstract

Both pharmacological studies on human patients and the analysis of animal models indicate that many forms of epilepsy involve dysfunction of neuron systems that use gamma-aminobutyric acid (GABA) as a principal neurotransmitter. The purpose of this project is to use recombinant DNA techniques to isolate the genes coding for two proteins that are central to GABA-ergic functions -- glutamic acid decarboxylase (GAD) and GABA receptor (GABA-R). Altered structures of these genes may be responsible for the inheritance of some forms of epilepsy. This project will test three hypotheses: 1. A gene coding for a GAD or GABA-R polypeptide is the site of the genetic lesion in Juvenile Myoclonic Epilepsy (JME). 2. The structure and expression of one of the GAD or GABA-R genes is altered in the existing genetic animal models of epilepsy (seizure-sensitive gerbils, audiogenic seizure sensitive mice, and tottering mice). 3. Epilepsy can be produced in mice by specifically blocking the expression of the genes for GAD or GABA-R. In order to test these hypotheses, we propose to employ recombinant DNA techniques now in use in this laboratory. We propose to isolate the genes for GAD and GABA-R and to study their structure and inheritance both in experimental animals and in families with JME. We will also attempt to develop new methods to study the functions of the candidate genes in tissue culture cells and in transgenic mice.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022256-02
Application #
3404464
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1985-04-01
Project End
1988-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

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

  Publications

Zanjani, Hadi; Lemaigre-Dubreuil, Y; Tillakaratne, Niranjala J K et al. (2004) Cerebellar Purkinje cell loss in aging Hu-Bcl-2 transgenic mice. J Comp Neurol 475:481-92
Carlson, B B; Behrstock, S; Tobin, A J et al. (2003) Brain implantations of engineered GABA-releasing cells suppress tremor in an animal model of Parkinsonism. Neuroscience 119:927-32
Tillakaratne, Niranjala J K; de Leon, Ray D; Hoang, Thao X et al. (2002) Use-dependent modulation of inhibitory capacity in the feline lumbar spinal cord. J Neurosci 22:3130-43
Tillakaratne, N J; Mouria, M; Ziv, N B et al. (2000) Increased expression of glutamate decarboxylase (GAD(67)) in feline lumbar spinal cord after complete thoracic spinal cord transection. J Neurosci Res 60:219-30
Thompson, K; Anantharam, V; Behrstock, S et al. (2000) Conditionally immortalized cell lines, engineered to produce and release GABA, modulate the development of behavioral seizures. Exp Neurol 161:481-9
Behrstock, S P; Anantharam, V; Thompson, K W et al. (2000) Conditionally-immortalized astrocytic cell line expresses GAD and secretes GABA under tetracycline regulation. J Neurosci Res 60:302-10
Srinivasan, S; Sapp, D W; Tobin, A J et al. (1999) Biphasic modulation of GABA(A) receptor binding by steroids suggests functional correlates. Neurochem Res 24:1363-72
Mi, J; Chatterjee, S; Wong, K K et al. (1999) Recombinant adeno-associated virus (AAV) drives constitutive production of glutamate decarboxylase in neural cell lines. J Neurosci Res 57:137-48
Srinivasan, S; Nichols, C J; Lawless, G M et al. (1999) Two invariant tryptophans on the alpha1 subunit define domains necessary for GABA(A) receptor assembly. J Biol Chem 274:26633-8
Banerjee, P K; Olsen, R W; Tillakaratne, N J et al. (1998) Absence seizures decrease steroid modulation of t-[35S]butylbicyclophosphorothionate binding in thalamic relay nuclei. J Pharmacol Exp Ther 287:766-72

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