Phosphorylation of GABAA receptor β3 subunit at Ser408–409 is essential for contextual learning at hippocampal CA1 synapses
Abstract Contextual learning requires strengthening at both AMPA receptor-mediated excitatory synapses and GABAA receptor-mediated inhibitory synapses in CA1 neurons. However, the precise mechanisms underlying learning-induced strengthening at inhibitory synapses have remained unclear. To address th...
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Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-07637-8 |
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| author | Yuya Sakimoto Yuheng Yang Hiroyuki Kida Dai Mitsushima |
| author_facet | Yuya Sakimoto Yuheng Yang Hiroyuki Kida Dai Mitsushima |
| author_sort | Yuya Sakimoto |
| collection | DOAJ |
| description | Abstract Contextual learning requires strengthening at both AMPA receptor-mediated excitatory synapses and GABAA receptor-mediated inhibitory synapses in CA1 neurons. However, the precise mechanisms underlying learning-induced strengthening at inhibitory synapses have remained unclear. To address this, we developed a novel cell-permeable peptide (Tat-pep β3-SS) that inhibits phosphorylation of the GABAA receptor β3 subunit at Ser408–409, using an HIV-Tat–tagged sequence. In behavioral experiments, bilateral microinjection of Tat-pep β3-SS into the CA1 region 60 min prior to inhibitory avoidance (IA) training significantly impaired contextual learning performance without affecting sensory, motor, and emotional functions. Western blot analysis revealed that Tat-pep β3-SS, but not the mutant control peptide (Tat-pep β3-AA), suppressed training-induced rapid phosphorylation at Ser408–409. Patch-clamp recordings from FITC-labeled CA1 neurons showed that Tat-pep β3-SS blocked learning-induced enhancement of postsynaptic Cl⁻ currents mediated by GABAA receptors. Furthermore, histological analysis demonstrated a reduction in membrane-associated GABAA receptor clusters in Tat-pep β3-SS–positive neurons compared to Tat-pep β3-AA controls. These findings provide novel evidence that rapid phosphorylation of the GABAA receptor β3 subunit at Ser408–409 is essential for training-dependent inhibitory synaptic strengthening and contextual memory formation. |
| format | Article |
| id | doaj-art-d4f4e92e6e2e41d1bea92285d5b2617e |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-d4f4e92e6e2e41d1bea92285d5b2617e2025-08-20T03:03:28ZengNature PortfolioScientific Reports2045-23222025-07-0115111210.1038/s41598-025-07637-8Phosphorylation of GABAA receptor β3 subunit at Ser408–409 is essential for contextual learning at hippocampal CA1 synapsesYuya Sakimoto0Yuheng Yang1Hiroyuki Kida2Dai Mitsushima3Department of Physiology, Yamaguchi University Graduate School of MedicineDepartment of Physiology, Yamaguchi University Graduate School of MedicineDepartment of Physiology, Yamaguchi University Graduate School of MedicineDepartment of Physiology, Yamaguchi University Graduate School of MedicineAbstract Contextual learning requires strengthening at both AMPA receptor-mediated excitatory synapses and GABAA receptor-mediated inhibitory synapses in CA1 neurons. However, the precise mechanisms underlying learning-induced strengthening at inhibitory synapses have remained unclear. To address this, we developed a novel cell-permeable peptide (Tat-pep β3-SS) that inhibits phosphorylation of the GABAA receptor β3 subunit at Ser408–409, using an HIV-Tat–tagged sequence. In behavioral experiments, bilateral microinjection of Tat-pep β3-SS into the CA1 region 60 min prior to inhibitory avoidance (IA) training significantly impaired contextual learning performance without affecting sensory, motor, and emotional functions. Western blot analysis revealed that Tat-pep β3-SS, but not the mutant control peptide (Tat-pep β3-AA), suppressed training-induced rapid phosphorylation at Ser408–409. Patch-clamp recordings from FITC-labeled CA1 neurons showed that Tat-pep β3-SS blocked learning-induced enhancement of postsynaptic Cl⁻ currents mediated by GABAA receptors. Furthermore, histological analysis demonstrated a reduction in membrane-associated GABAA receptor clusters in Tat-pep β3-SS–positive neurons compared to Tat-pep β3-AA controls. These findings provide novel evidence that rapid phosphorylation of the GABAA receptor β3 subunit at Ser408–409 is essential for training-dependent inhibitory synaptic strengthening and contextual memory formation.https://doi.org/10.1038/s41598-025-07637-8 |
| spellingShingle | Yuya Sakimoto Yuheng Yang Hiroyuki Kida Dai Mitsushima Phosphorylation of GABAA receptor β3 subunit at Ser408–409 is essential for contextual learning at hippocampal CA1 synapses Scientific Reports |
| title | Phosphorylation of GABAA receptor β3 subunit at Ser408–409 is essential for contextual learning at hippocampal CA1 synapses |
| title_full | Phosphorylation of GABAA receptor β3 subunit at Ser408–409 is essential for contextual learning at hippocampal CA1 synapses |
| title_fullStr | Phosphorylation of GABAA receptor β3 subunit at Ser408–409 is essential for contextual learning at hippocampal CA1 synapses |
| title_full_unstemmed | Phosphorylation of GABAA receptor β3 subunit at Ser408–409 is essential for contextual learning at hippocampal CA1 synapses |
| title_short | Phosphorylation of GABAA receptor β3 subunit at Ser408–409 is essential for contextual learning at hippocampal CA1 synapses |
| title_sort | phosphorylation of gabaa receptor β3 subunit at ser408 409 is essential for contextual learning at hippocampal ca1 synapses |
| url | https://doi.org/10.1038/s41598-025-07637-8 |
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