Role of GABAA receptors in cognition
Abstract
Complex brains have developed specialized mechanisms for the grouping of principal cells into temporal coalitions of local or distant networks: the inhibitory interneuron 'clocking' networks. They consist of GABAergic (where GABA is gamma-aminobutyric acid) interneurons of a rich diversity. In cortical circuits, these neurons control spike timing of the principal cells, sculpt neuronal rhythms, select cell assemblies and implement brain states. On the basis of these considerations, the deficits in cognition, emotion and perception in psychiatric disorders such as anxiety, depression or schizophrenia are considered to manifest themselves through a dysregulation of the inhibitory interneuron 'clocking' network as a final common denominator, irrespective of the diverse underlying disease pathologies. The diversity of GABAergic interneurons is paralleled by a corresponding diversity of GABA(A) receptors in network regulation. The region-, cell- and domain-specific location of these receptor subtypes offers the possibility to gain functional insights into the role of behaviourally relevant neuronal circuits. Using genetic manipulation, the regulation of anxiety behaviour was attributed to neuronal circuits characterized by the expression of alpha(2)-GABA(A) receptors. Neurons expressing alpha(3)-GABA(A) receptors, located mainly in aminergic and basal forebrain cholinergic neurons, were related to a hyperdopaminergic phenotype, typical of schizophrenic symptoms. Temporal and spatial memory were selectively modulated by extrasynaptic alpha(5)-GABA(A) receptors. Chronic pathological pain was under the regulation of spinal and cortical alpha(2)- (and alpha(3)-) GABA(A) receptors. Thus the relevance of the diversity of inhibitory GABA(A) receptor subtypes for the regulation of cognition, emotion and memory is increasingly being recognized. The clinical proof-of-concept of a subtype-specific pharmacology is most advanced for the alleviation of cognitive dysfunctions in schizophrenia, based on the treatment of patients with an alpha(2)/alpha(3)-GABA(A) receptor ligand.
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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 [60]
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Self-citation
- Authors
- Möhler, H.
- Affiliations
- University of Zurich (CH)
- Corresponding author
- Möhler, Hanns
- Venue
- Biochemical Society Transactions
- Publisher
- Portland Press Ltd.
- Published
- 2009-11-19
- Volume
- 37
- Issue
- 6
- Pages
- 1328-1333
- ISSN
- 0300-5127 (ISSN-L)
- 1470-8752
- OpenAlex
- W2078535830
- Cited by
- 79
- References
- 55
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 1 · 2022: 5 · 2021: 7 · 2020: 6 · 2019: 3 · 2018: 7 · 2017: 4 · 2016: 5 · 2015: 9 · 2014: 5 · 2013: 7 · 2012: 2
- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Society Transactions (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- GABAA receptor, GABAergic interneurons, alpha5 GABA-A receptor, extrasynaptic GABAA receptors, schizophrenia, anxiety, depression, memory, pathological pain, dopaminergic neurons, cognitive impairment
- MeSH terms
- Animals, Anxiety, Brain, Cognition, Electroencephalography, gamma-Aminobutyric Acid, Humans, Interneurons, Learning, Ligands, Memory, Nerve Net, Pain, Receptors, GABA-A, Schizophrenia, Sleep, Protein Isoforms, Mice
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