GABAA receptors (GABAARs) mediate fast inhibition and slow, tonic inhibition. GABAARs are the target of clinically important anxiolytics, as well as anticonvulsants and anesthetics. Past work implicates high-affinity extrasynaptic GABAAR subunit combinations in tonic currents and low-affinity, synaptic populations in phasic IPSCs. This past work supports the prevailing view that low GABA affinity prevents a major role of synaptic receptors in tonic currents. However, consideration of the large number of synaptic receptors in hippocampal neurons raises questions about why synaptic receptors do not contribute to tonic currents in spite of their low GABA sensitivity. To explain discrepancies between prevailing views and our calculations and preliminary observations, we hypothesize that a major overlooked role of GABA transporters is to protect synaptic receptors from ambient GABA buildup and to prevent synaptic receptor contributions to tonic currents. Support for this hypothesis would significantly alter a prevailing explanation for tonic currents and would suggest that receptor properties alone cannot explain the nearly exclusive contribution of high-affinity extrasynaptic receptors to tonic currents. To test our hypothesis, we will leverage novel pharmacological tools that our laboratory has recently characterized.
Aim 1 will test a role for GAT-1 transporters in shielding synaptic receptors from ambient GABA.
Aim 2 will test the physiological implications for excitability and for positive allosteric modulation of tonic current mediated by high affinity extrasynaptic receptors versus low-affinity synaptic receptors.

Public Health Relevance

GABAA receptors (GABAARs) are the target of clinically important anxiolytics, as well as anticonvulsants and anesthetics. To understand how the drugs have their behavioral and clinical actions, we need to understand the role of target GABAARs in fast and slow inhibition. This proposal takes a fresh look at why slow GABAAR inhibition arises from particular receptor classes and not others. We also examine the implications for excitability of slow signaling through specific receptor populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH099658-02
Application #
8597463
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Asanuma, Chiiko
Project Start
2012-12-15
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$171,000
Indirect Cost
$58,500
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Eaton, Megan M; Bracamontes, John; Shu, Hong-Jin et al. (2014) ?-aminobutyric acid type A ?4, ?2, and ? subunits assemble to produce more than one functionally distinct receptor type. Mol Pharmacol 86:647-56
Chen, Zi-Wei; Wang, Cunde; Krishnan, Kathiresan et al. (2014) 11-trifluoromethyl-phenyldiazirinyl neurosteroid analogues: potent general anesthetics and photolabeling reagents for GABAA receptors. Psychopharmacology (Berl) 231:3479-91
Mennerick, Steven; Taylor, Amanda A; Zorumski, Charles F (2014) Phosphatidylinositol 4,5-bisphosphate depletion fails to affect neurosteroid modulation of GABAA receptor function. Psychopharmacology (Berl) 231:3493-501