Abstract
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 environment 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 integral leaflet-structural protein, from hippocampal astrocytes using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing. Next, a combination of Föster 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.
Original language | English |
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Pages (from-to) | 226-238 |
Number of pages | 13 |
Journal | Biological psychiatry |
Volume | 94 |
Issue number | 3 |
Early online date | 29 Oct 2022 |
DOIs | |
Publication status | Published - 1 Aug 2023 |
Bibliographical note
Funding Information:AB-S received funding from the EU-FP7-PEOPLE program (CognitionNET; Grant No. 607509). MSJK received funding from ZonMW Memorable (Grant No. 7330508160).
Publisher Copyright:
© 2022 Society of Biological Psychiatry
Keywords
- CRISPR/Cas9
- Ezrin
- Fear memory
- Glia
- Glutamate spillover
- Synapse