Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory
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Neurotransmitter receptor density is a major variable in regulating synaptic strength. Receptors rapidly exchange between synapses and intracellular storage pools through endocytic recycling. In addition, lateral diffusion and confinement exchanges surface membrane receptors between synaptic and extrasynaptic sites. However, the signals that regulate this transition are currently unknown. GABAA receptors containing α5-subunits (GABAAR-α5) concentrate extrasynaptically through radixin (Rdx)-mediated anchorage at the actin cytoskeleton. Here we report a novel mechanism that regulates adjustable plasma membrane receptor pools in the control of synaptic receptor density. RhoA/ROCK signalling regulates an activity-dependent Rdx phosphorylation switch that uncouples GABAAR-α5 from its extrasynaptic anchor, thereby enriching synaptic receptor numbers. Thus, the unphosphorylated form of Rdx alters mIPSCs. Rdx gene knockout impairs reversal learning and short-term memory, and Rdx phosphorylation in wild-type mice exhibits experience-dependent changes when exposed to novel environments. Our data suggest an additional mode of synaptic plasticity, in which extrasynaptic receptor reservoirs supply synaptic GABAARs.
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Knockout of the extrasynaptic anchoring protein radixin leads to a shift in the expression of α5GABAARs from extrasynaptic to synaptic positions.
“Similarly, knockout of the extrasynaptic anchoring protein radixin leads to a shift in the expression of α5GABAARs from extrasynaptic to synaptic positions, and results in deficits in reversal learning [81]”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [81]
Knockout of radixin results in deficits in reversal learning.
“Similarly, knockout of the extrasynaptic anchoring protein radixin leads to a shift in the expression of α5GABAARs from extrasynaptic to synaptic positions, and results in deficits in reversal learning [81]”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [81]
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- Authors
- Hausrat, T. J., Muhia, M., Gerrow, K., Thomas, P., Hirdes, W., Tsukita, S., Heisler, F. F., Herich, L., Dubroqua, S., Breiden, P., Feldon, J., Schwarz, J. R., Yee, B. K., Smart, T. G., Triller, A., & Kneussel, M.
- Affiliations
- University Medical Center Hamburg-Eppendorf (DE)
- Centre National de la Recherche Scientifique (FR)
- University College London (GB)
- The University of Osaka (JP)
- ETH Zurich (CH)
- Corresponding author
- Kneussel, Matthias
- ORCID
- Venue
- Nature Communications
- Published
- 2015-04-20
- Volume
- 6
- Issue
- 1
- Pages
- 6872-6872
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4411296
- OpenAlex
- W2032730889
- Cited by
- 138
- References
- 52
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 11 · 2023: 9 · 2022: 21 · 2021: 21 · 2020: 9 · 2019: 16 · 2018: 7 · 2017: 14 · 2016: 8
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- ETH Zürich Research Collection (cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (GRK 1459, KN556/6-1)
- Agence Nationale de la Recherche (10-LABX-54, ANR–10–LABX–54, ANR-10)
- Chica and Heinz Schaller Foundation
- Medical Research Council (MR/K005537/1)
- Universitätsklinikum Hamburg-Eppendorf
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- radixin, GABAA receptor, extrasynaptic receptors, RhoA/ROCK signaling, receptor phosphorylation, synaptic plasticity, reversal learning, short-term memory, miniature inhibitory postsynaptic currents, receptor recycling, experience-dependent plasticity
- MeSH terms
- Animals, Cytoskeletal Proteins, Gene Expression Regulation, Hippocampus, Learning, Membrane Proteins, Receptors, GABA-A, Synapses, Mice, Knockout, Mice, Electrophysiological Phenomena
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