Retraction of Astrocyte Leaflets From the Synapse Enhances Fear Memory
Retraction of Astrocyte Leaflets From the Synapse Enhances Fear Memory
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DOI：
10.1016/j.biopsych.2022.10.013
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发表时间：
2023-07-10
影响因子：
10.6
通讯作者：
Verheijen, Mark H. G.
中科院分区：
文献类型：
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作者：
Badia-Soteras, Aina;Heistek, Tim S.;Verheijen, Mark H. G.
背景：恐惧记忆的形成和检索取决于海马内神经元群精心策划的突触活动，并且越来越明显的是，居住在这些突触环境中的星形胶质细胞在塑造细胞记忆表征中发挥着核心作用。星形胶质细胞远端突起（称为小叶）通过清除神经递质和限制谷氨酸扩散来微调突触活动。然而，星形胶质细胞突触覆盖如何促进恐惧经历的记忆处理仍然很大程度上未知。方法：我们使用电子显微镜观察小鼠恐惧记忆巩固过程中海马突触星形胶质细胞覆盖的变化。为了操纵星形胶质细胞突触覆盖，我们使用 CRISPR（成簇规则间隔短回文重复序列）/Cas9 基因编辑从海马星形胶质细胞中去除了 ezrin（一种整体小叶结构蛋白）。接下来，结合福斯特共振能量转移分析、基因编码的谷氨酸传感器和全细胞膜片钳记录来确定星形胶质细胞小叶与突触的接近程度是否对突触完整性和功能至关重要。结果：我们发现，近期恐惧记忆的巩固伴随着星形胶质细胞小叶从海马突触的短暂回缩和激活增加。 NMDA 受体。因此，星形胶质细胞特异性消耗埃兹蛋白会导致星形胶质细胞小叶变短，并减少星形胶质细胞与突触间隙的接触，从而促进突触外谷氨酸扩散和 NMDA 受体激活。重要的是，在恐惧条件作用后，这些细胞表型转化为 CA1 锥体神经元检索诱发的激活增加，并增强恐惧记忆表达。结论：总的来说，我们的数据表明，星形胶质细胞小叶从突触间隙的撤回是一个经验诱导的、时间调节的过程，它控制着恐惧记忆的强度。
BACKGROUND: The formation and retrieval of fear memories depends on orchestrated synaptic activity of neuronal ensembles within the hippocampus, and it is becoming increasingly evident that astrocytes residing in the envi-ronment of these synapses play a central role in shaping cellular memory representations. Astrocyte distal processes, known as leaflets, fine-tune synaptic activity by clearing neurotransmitters and limiting glutamate diffusion. However, how astroglial synaptic coverage contributes to mnemonic processing of fearful experiences remains largely unknown. METHODS: We used electron microscopy to observe changes in astroglial coverage of hippocampal synapses during consolidation of fear memory in mice. To manipulate astroglial synaptic coverage, we depleted ezrin, an in-tegral leaflet-structural protein, from hippocampal astrocytes using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing. Next, a combination of Foster resonance energy transfer analysis, genetically encoded glutamate sensors, and whole-cell patch-clamp recordings was used to determine whether the proximity of astrocyte leaflets to the synapse is critical for synaptic integrity and function.RESULTS: We found that consolidation of a recent fear memory is accompanied by a transient retraction of astrocyte leaflets from hippocampal synapses and increased activation of NMDA receptors. Accordingly, astrocyte-specific depletion of ezrin resulted in shorter astrocyte leaflets and reduced astrocyte contact with the synaptic cleft, which consequently boosted extrasynaptic glutamate diffusion and NMDA receptor activation. Importantly, after fear conditioning, these cellular phenotypes translated to increased retrieval-evoked activation of CA1 pyramidal neurons and enhanced fear memory expression.CONCLUSIONS: Together, our data show that withdrawal of astrocyte leaflets from the synaptic cleft is an experience-induced, temporally regulated process that gates the strength of fear memories.