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 : We will test the hypothesis that synaptic and extrasynaptic GABAA receptors have different rates of lateral mobility.
Specific Aim 2 : We will 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 approaches will 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 #
1R01NS051195-01A1
Application #
7029388
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
Project Start
2006-03-15
Project End
2010-01-31
Budget Start
2006-03-15
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$437,385
Indirect Cost
Name
University of Pennsylvania
Department
Neurosciences
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Rifkin, Robert A; Moss, Stephen J; Slesinger, Paul A (2017) G Protein-Gated Potassium Channels: A Link to Drug Addiction. Trends Pharmacol Sci 38:378-392
Modgil, Amit; Parakala, Manasa L; Ackley, Michael A et al. (2017) Endogenous and synthetic neuroactive steroids evoke sustained increases in the efficacy of GABAergic inhibition via a protein kinase C-dependent mechanism. Neuropharmacology 113:314-322
Mukherjee, Jayanta; Cardarelli, Ross A; Cantaut-Belarif, Yasmine et al. (2017) Estradiol modulates the efficacy of synaptic inhibition by decreasing the dwell time of GABAA receptors at inhibitory synapses. Proc Natl Acad Sci U S A 114:11763-11768
Kang, Ji-Yong; Chadchankar, Jayashree; Vien, Thuy N et al. (2017) Deficits in the activity of presynaptic ?-aminobutyric acid type B receptors contribute to altered neuronal excitability in fragile X syndrome. J Biol Chem 292:6621-6632
Wobst, Heike J; Wesolowski, Steven S; Chadchankar, Jayashree et al. (2017) Cytoplasmic Relocalization of TAR DNA-Binding Protein 43 Is Not Sufficient to Reproduce Cellular Pathologies Associated with ALSIn vitro. Front Mol Neurosci 10:46
Trattnig, Sarah M; Gasiorek, Agnes; Deeb, Tarek Z et al. (2016) Copper and protons directly activate the zinc-activated channel. Biochem Pharmacol 103:109-17
Saito, A; Taniguchi, Y; Rannals, M D et al. (2016) Early postnatal GABAA receptor modulation reverses deficits in neuronal maturation in a conditional neurodevelopmental mouse model of DISC1. Mol Psychiatry 21:1449-59
Nakamura, Yasuko; Morrow, Danielle H; Modgil, Amit et al. (2016) Proteomic Characterization of Inhibitory Synapses Using a Novel pHluorin-tagged ?-Aminobutyric Acid Receptor, Type A (GABAA), ?2 Subunit Knock-in Mouse. J Biol Chem 291:12394-407
Vien, Thuy N; Moss, Stephen J; Davies, Paul A (2016) Regulating the Efficacy of Inhibition Through Trafficking of ?-Aminobutyric Acid Type A Receptors. Anesth Analg 123:1220-1227
Kelley, Matthew R; Deeb, Tarek Z; Brandon, Nicholas J et al. (2016) Compromising KCC2 transporter activity enhances the development of continuous seizure activity. Neuropharmacology 108:103-10

Showing the most recent 10 out of 77 publications