GABA (?y-aminobutyric acid) is the major inhibitory neurotransmitter in the mammalian nervous system. The fast synaptic inhibitory action of GABA is due largely to the activation of GABAA receptors, which are Cl~ permeable ligand-gated ion channels. These receptors are also targets for several clinically important drug classes, including benzodiazepines, barbiturates, neurosteroids and general anesthetics. Modifications of GABAA receptor function have been implicated in a range of CNS pathologies. It is essential for efficient synaptic transmission that GABAA receptors are clustered and stabilized at postsynaptic sites opposed to presynaptic GABAergic terminals. However, the mechanisms that underlie the selective accumulation and stabilization of these receptors at synaptic localizations remain unknown. We hypothesize that synaptic GABAA receptors, as opposed to extrasynaptic receptor populations, exhibit reduced lateral mobilities and enhance surface stabilities and that this difference in dynamic behavior is regulated by gephyrin, a protein implicated in the formation of inhibitory synapses. Thus we will use a combination of cell biology and biochemical approaches to carry out three independent but related specific aims:
Specific Aim 1 : Wewill test the hypothesis that synaptic and extrasynaptic GABAA receptors have different rates of lateral mobility.
Specific Aim 2 : Wewill test the hypothesis that synaptic and extrasynaptic GABAA receptors have different cell surface stabilities.
Specific Aim 3 : We will test the hypothesis that gephyrin regulates GABAA receptor mobility and cell surface stability at inhibitory synapses. Together, our approacheswill provide a more thorough understanding of the primary determinants that regulate accumulation of GABAA receptors at synaptic sites. The results of these studies will have the potential to make significant contributions to the development of novel therapeutic strategies for such debilitating disorders as epilepsy, anxiety,addiction, autism, and mental retardation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051195-03
Application #
7355549
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
Project Start
2006-03-15
Project End
2008-05-31
Budget Start
2008-02-01
Budget End
2008-05-31
Support Year
3
Fiscal Year
2008
Total Cost
$110,116
Indirect Cost
Name
University of Pennsylvania
Department
Neurosciences
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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