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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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
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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| Summary: | 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. |
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| ISSN: | 2045-2322 |