Soh Ming Shiuan, Lynch Joseph W
Queensland Brain Institute, The University of Queensland, Brisbane 4072, Queensland, Australia.
Curr Drug Targets. 2015;16(7):735-46. doi: 10.2174/1389450116666150309120235.
GABAA receptors containing the α5 subunit (5GABAARs) are found mainly in the hippocampus where they mediate a tonic chloride leak current and contribute a slow component to GABAergic inhibitory synaptic currents. Their inhibitory effect on the excitability of hippocampal neurons at least partly explains why changes in the level of activity of 5GABAARs affect cognition, learning and memory. These receptors have been implicated as potential therapeutic targets for a range of clinical conditions including age-related dementia, stroke, schizophrenia, Down syndrome and anesthetic- induced amnesia. Accordingly, a range of pharmacological modulators that selectively target 5GABAARs, as either inhibitors or allosteric enhancers, have been developed. Although many of these compounds show therapeutic effects in animal models of the above clinical disorders, none has been marketed yet due to unsuccessful clinical trials and toxicity in humans. These experiments have also revealed paradoxical effects of 5GABAAR modulation (e.g., cognitive impairments can be reversed by both positive and negative modulation), suggesting that our knowledge of the physiological roles of 5GABAARs is incomplete. This review highlights the various positive and negative modulators for 5GABAARs that have been developed, key findings concerning their effects in behavioral studies, and their importance across a number of therapeutic fields. It also highlights some of the gaps in our knowledge of the physiological and pathological roles of α5GABAARs.
含有α5亚基的GABAA受体（α5GABAARs）主要存在于海马体中，它们介导持续性氯化物泄漏电流，并对GABA能抑制性突触电流产生缓慢成分。它们对海马神经元兴奋性的抑制作用至少部分解释了为什么α5GABAARs活性水平的变化会影响认知、学习和记忆。这些受体已被认为是一系列临床病症的潜在治疗靶点，包括与年龄相关的痴呆症、中风、精神分裂症、唐氏综合征和麻醉诱导的失忆症。因此，已经开发出一系列选择性靶向α5GABAARs的药理学调节剂，作为抑制剂或变构增强剂。尽管这些化合物中的许多在上述临床疾病的动物模型中显示出治疗效果，但由于临床试验失败和对人类的毒性，尚无一种上市。这些实验还揭示了α5GABAAR调节的矛盾效应（例如，正向和负向调节均可逆转认知障碍），这表明我们对α5GABAARs生理作用的了解并不完整。本综述重点介绍了已开发的α5GABAARs的各种正向和负向调节剂、它们在行为研究中的作用的关键发现以及它们在多个治疗领域的重要性。它还突出了我们在α5GABAARs生理和病理作用知识方面的一些空白。
