RECEPTOR POPULATIONS UNDERLYING TONIC GABA CURRENTS IN HIPPOCAMPUS

描述(由申请人提供)：GABAA受体(GABAARs)介导快速抑制和缓慢、紧张性抑制。GABAARs是临床上重要的抗焦虑药物以及抗惊厥药物和麻醉药的靶标。过去的工作表明，在时相IPSCs中，张力电流中存在高亲和力的突触外GABAAR亚单位组合，而低亲和力的突触群体中存在GABAAR亚单位。过去的工作支持了流行的观点，即低GABA亲和力阻止了突触受体在紧张性电流中的主要作用。然而，考虑到海马神经元中大量的突触受体，人们提出了这样一个问题：为什么突触受体尽管对GABA的敏感性很低，但并不对紧张性电流起作用。为了解释主流观点与我们的计算和初步观察之间的差异，我们假设GABA转运体的一个主要被忽视的作用是保护突触受体免受周围GABA积聚的影响，并防止突触受体对紧张性电流的贡献。对这一假说的支持将极大地改变对紧张性电流的普遍解释，并表明仅凭受体的特性并不能解释高亲和力突触外受体对紧张性电流的几乎唯一贡献。为了验证我们的假设，我们将利用我们实验室最近表征的新型药理学工具。目标1将测试GAT-1转运体在屏蔽突触受体免受环境GABA影响方面的作用。目的2将测试高亲和力突触外受体和低亲和力突触受体介导的兴奋性和正变构调节紧张性电流的生理学意义。

DESCRIPTION (provided by applicant): 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.