Scholarlink

<p>Contextual learning requires strengthening at both AMPA receptor-mediated excitatory synapses and GABA<sub>A</sub> 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 β<sub>3</sub>-<i>SS</i>) that inhibits phosphorylation of the GABA<sub>A</sub> receptor β<sub>3</sub> subunit at Ser<sup>408–409</sup>, using an HIV-Tat–tagged sequence. In behavioral experiments, bilateral microinjection of Tat-pep β<sub>3</sub>-<i>SS</i> into the CA1 region 60&#xa0;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 β<sub>3</sub>-<i>SS</i>, but not the mutant control peptide (Tat-pep β<sub>3</sub>-<i>AA</i>), suppressed training-induced rapid phosphorylation at Ser<sup>408–409</sup>. Patch-clamp recordings from FITC-labeled CA1 neurons showed that Tat-pep β<sub>3</sub>-<i>SS</i> blocked learning-induced enhancement of postsynaptic Cl⁻ currents mediated by GABA<sub>A</sub> receptors. Furthermore, histological analysis demonstrated a reduction in membrane-associated GABA<sub>A</sub> receptor clusters in Tat-pep β<sub>3</sub>-<i>SS</i>–positive neurons compared to Tat-pep β<sub>3</sub>-<i>AA</i> controls. These findings provide novel evidence that rapid phosphorylation of the GABA<sub>A</sub> receptor β<sub>3</sub> subunit at Ser<sup>408–409</sup> is essential for training-dependent inhibitory synaptic strengthening and contextual memory formation.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Phosphorylation of GABAA receptor β3 subunit at Ser408–409 is essential for contextual learning at hippocampal CA1 synapses

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月1日

查看全文
  • Yuya Sakimoto,
  • Yuheng Yang,
  • Hiroyuki Kida,
  • Dai Mitsushima

摘要

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.