Selective Modulators of α5-Containing GABAA Receptors and their Therapeutic Significance
Abstract
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.
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α5GABAARs have been implicated most consistently in memory, with knockdown, knockout, or pharmacological suppression of α5GABAARs leading to improvements in learning and memory.
“α5GABAARs, which are expressed most intensively in the hippocampus and deep layers of cortex, have been implicated most consistently in memory, with knockdown, knockout, or pharmacological suppression of α5GABAARs leading to improvements in learning and memory [56-61].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [61]
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“The α5-containing GABAAR subtypes in the hippocampus play an important role in cognition, learning and memory (Caraiscos et al., 2004; Soh and Lynch, 2015).”
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“This suggests that memory enhancement associated with administration of the 5-GABAAR inhibitors may arise from the removal of tonic (Atack et al., 2006; Braudeau et al., 2011; Soh and Lynch, 2015) and phasic inhibition (Hausrat et al.”
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“Because these subunits are present mainly in the hippocampus, the inhibition of these receptors could be of interest in different pathologies such as dementia, schizophrenia, and Down syndrome [143].”
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“α5 GABAARs are highly sensitive to GABA and show a slow desensitization rate (Soh and Lynch, 2015), allowing them to mediate the tonic inhibition regulated by the low-concentration ambient GABA that exists outside of hippocampal neuronal synapses (Caraiscos et al.”
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- Authors
- Soh, M., & Lynch, J.
- Affiliations
- The University of Queensland (AU)
- Venue
- Current Drug Targets
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2015-07-27
- Volume
- 16
- Issue
- 7
- Pages
- 735-746
- ISSN
- 1389-4501 (ISSN-L)
- OpenAlex
- W2012872188
- Cited by
- 27
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 3 · 2019: 5 · 2018: 5 · 2017: 4 · 2016: 1 · 2015: 1
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Drug Targets (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- alpha5 GABA-A receptor, GABA-A receptor modulators, allosteric enhancers, positive modulators, hippocampus, tonic inhibition, cognitive impairment, age-related dementia, schizophrenia, Down syndrome, stroke, paradoxical effects, drug toxicity
- MeSH terms
- Amnesia, Animals, Cognition Disorders, Humans, Receptors, GABA-A, GABA Modulators, Stroke
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