Knock-in mice were generated by replacing the native alpha4 subunit of the nicotinic acetylcholine receptors (nAChR), with a mutated form that responds that responds to lower than normal concentrations of acetylcholine and nicotine. Within the general objective of characterizing nAChR function,, the focus of this project is to study the mechanisms by which changes in the mutated receptor-channel lead to seizure induction hypertensity. The L9'S mutation of the alpha4 subunit causes a 30-fold increase in nAChRs response to acetylcholine, nicotine and choline. The LP'S mutation of the alpha4 subunit causes a 30-fold increase in nAChRs response to acetylcholine, nicotine and choline. The mutated alpha4 mice display severe seizures upon nAChRs stimulation. Considering the phenotypic characteristics of these mice, and the similarity of t he present alpha4 mutation to point mutations in human alpha4 that cause the epileptic pathology ADNFLE, it is suggested that this project is relevant to the study of epilepsies. The following experimental objectives are proposed to examine the relationship between a gain of function mutation in the alpha4 subunit and seizure induction: 1) To study the behavior and record the electroencephalographic patterns of L9'S mice treated with nicotinic and convulsive compounds. 2) To examine th effects of the L9'S mice treated with nicotinic and convulsive compounds. 2) To examine the effects of the LP'S transmission using brain tissue slices. 3) To determine the effects of the LP'S mutation of nAChR activation/desensitization, and synaptic properties of cultured neurons by doing whole-cell patch clamp recordings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS043944-03
Application #
6762399
Study Section
Special Emphasis Panel (ZRG1-F01 (20))
Program Officer
Stewart, Randall R
Project Start
2002-05-01
Project End
2005-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
3
Fiscal Year
2004
Total Cost
$50,406
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125