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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Asanuma, Chiiko
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Washington University
Schools of Medicine
Saint Louis
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Sobieski, Courtney; Fitzpatrick, Michael J; Mennerick, Steven J (2017) Differential Presynaptic ATP Supply for Basal and High-Demand Transmission. J Neurosci 37:1888-1899
Chakrabarti, Sampurna; Qian, Mingxing; Krishnan, Kathiresan et al. (2016) Comparison of Steroid Modulation of Spontaneous Inhibitory Postsynaptic Currents in Cultured Hippocampal Neurons and Steady-State Single-Channel Currents from Heterologously Expressed ?1?2?2L GABA(A) Receptors. Mol Pharmacol 89:399-406
Jiang, Xiaoping; Shu, Hong-Jin; Krishnan, Kathiresan et al. (2016) A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition. Neuropharmacology 108:193-206
Sobieski, Courtney; Jiang, Xiaoping; Crawford, Devon C et al. (2015) Loss of Local Astrocyte Support Disrupts Action Potential Propagation and Glutamate Release Synchrony from Unmyelinated Hippocampal Axon Terminals In Vitro. J Neurosci 35:11105-17
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