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.
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.
