MicroRNA‐138‐5p suppresses excitatory synaptic strength at the cerebellar input layer
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Abstract
MicroRNAs are small, highly conserved non‐coding RNAs that negatively regulate mRNA translation and stability. In the brain, miRNAs contribute to neuronal development, synaptogenesis, and synaptic plasticity. MicroRNA 138‐5p (miR‐138‐5p) controls inhibitory synaptic transmission in the hippocampus and is highly expressed in cerebellar excitatory neurons. However, its specific role in cerebellar synaptic transmission remains unknown. Here, we investigated excitatory transmission in the cerebellum of mice expressing a sponge construct that sequesters endogenous miR‐138‐5p. Mossy fibre stimulation‐evoked EPSCs in granule cells were ∼40% larger in miR‐138‐5p sponge mice compared to controls. Furthermore, we observed larger miniature EPSC amplitudes, suggesting an increased number of functional postsynaptic AMPA receptors. High‐frequency train stimulation revealed enhanced short‐term depression following miR‐138‐5p downregulation. Together with computational modelling, this suggests a negative regulation of presynaptic release probability. Overall, our results demonstrate that miR‐138‐5p suppresses synaptic strength through pre‐ and postsynaptic mechanisms, providing a potentially powerful mechanism for tuning excitatory synaptic input into the cerebellum. image Key points: MicroRNAs are powerful regulators of mRNA translation and control key cell biological processes including synaptic transmission, but their role in regulating synaptic function in the cerebellum has remained elusive. In this study, we investigated how microRNA‐138‐5p (miR‐138‐5p) modulates excitatory transmission at adult murine cerebellar mossy fibre to granule cell synapses. Downregulation of miR‐138‐5p enhances excitatory synaptic strength at the cerebellar input layer and increases short‐term depression. miR‐138‐5p exerts its regulatory function through both pre‐ and postsynaptic mechanisms by negatively regulating release probability at mossy fibre boutons, as well as functional AMPA receptor numbers in granule cells. These findings provide insights into the role of miR‐138‐5p in the cerebellum and expand our understanding of microRNA‐dependent control of excitatory synaptic transmission and short‐term plasticity.
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- Authors
- Delvendahl, I., Daswani, R., Winterer, J., Germain, P., Uhr, N. M., Schratt, G., & Müller, M.
- Affiliations
- University of Freiburg (DE)
- ETH Zurich (CH)
- University of Zurich (CH)
- Corresponding author
- Delvendahl, Igor
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2025-05
- Volume
- 603
- Issue
- 10
- Pages
- 3161-3179
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC12126606
- OpenAlex
- W4410272343
- Cited by
- 3
- References
- 86
- Citations by year
- 2026: 1 · 2025: 2
- FWCI
- 0.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Physiology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository for Publications and Research Data (ETH Zurich) (publishedVersion, cc-by)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- ETH Zürich Research Collection (cc-by)
- Funders
- National Science Foundation
- Deutsche Forschungsgemeinschaft (535029399)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (144816, 174018)
- Universität Zürich
- H2020 European Research Council (679881)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- cerebellum, excitatory synaptic transmission, synaptic efficacy, short-term depression, presynaptic release probability, AMPA receptors, miniature EPSCs, microRNA sponge, synaptic plasticity
- MeSH terms
- Animals, Cerebellum, Male, Mice, Inbred C57BL, Synaptic Transmission, Synapses, Receptors, AMPA, Excitatory Postsynaptic Potentials, MicroRNAs, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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