MicroRNA-218 instructs proper assembly of hippocampal networks
- Brigham Young University, United States
- Howard Hughes Medical Institute, Rockefeller University, United States
- University of Modena and Reggio Emilia, Italy
- Cincinnati Children's Hospital Medical Center, United States
- Scripps Research Institute, United States
- University of California, San Diego, United States
- Institute of Genetics and Biophysics A Buzzati-Traverso, Italy
Abstract
The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. Post-transcriptional regulation by microRNAs (miRNAs) is a key aspect of this program. Indeed, deletion of neuron-enriched miRNAs induces strong developmental phenotypes, and miRNA levels are altered in patients with neurodevelopmental disorders. However, the mechanisms used by miRNAs to instruct brain development remain largely unexplored. Here, we identified miR-218 as a critical regulator of hippocampal assembly. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons (PNs) and GABAergic inhibitory interneurons (INs). Early life inhibition of miR-218 results in an adult brain with a predisposition to seizures. Changes in gene expression in the absence of miR-218 suggest that network assembly is impaired. Indeed, we find that miR-218 inhibition results in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. Conditional knockout of Mir218-2 in INs, but not PNs, is sufficient to recapitulate long-term instability. Finally, de-repressing Kif21b and Syt13, two miR-218 targets, phenocopies the effects on early synchronous network activity induced by miR-218 inhibition. Taken together, the data suggest that miR-218 orchestrates formative events in PNs and INs to produce stable networks.
Data availability
RNA-seq data has been deposited to GEO (accession number GSE241245)
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MicroRNA-218 instructs proper assembly of hippocampal networksNCBI Gene Expression Omnibus, GSE241245.
Article and author information
Author details
Funding
National Institutes of Health (1 S10 OD026817-01)
- Giordano Lippi
Ministero dell'Istruzione, dell'Università e della Ricerca (1R01NS092705)
- Michele Zoli
National Institutes of Health (2R01NS012601)
- Darwin K Berg
National Institutes of Health (1R21NS087342)
- Darwin K Berg
National Institutes of Health (1R01NS121223)
- Giordano Lippi
National Institutes of Health (1R01NS092705)
- Christina Gross
Tobacco-Related Disease Research Program (22XT-0016,21FT-0027)
- Darwin K Berg
Whitehall Foundation (2018-12-55)
- Giordano Lippi
Autism Speaks (12923)
- Norjin Zolboot
American Epilepsy Society (12923)
- Andrea Hartzell
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- John R Huguenard, Stanford University School of Medicine, United States
Ethics
Animal experimentation: All experimental procedures at UCSD, CCHMH and SRI were performed as approved by the Institutional Animal Care and Use Committees and according to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Behavioral and in vivo experiments at UNIMORE were conducted in accordance with the European Community Council Directive (86/609/EEC) of November 24, 1986, and approved by the ethics committee (authorization number: 37/2018PR).
Version history
- Received: August 16, 2022
- Preprint posted: August 25, 2022 (view preprint)
- Accepted: October 10, 2023
- Accepted Manuscript published: October 20, 2023 (version 1)
- Version of Record published: November 10, 2023 (version 2)
Copyright
© 2023, Taylor et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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MicroRNA-218 instructs proper assembly of hippocampal networks
eLife 12:e82729.
https://doi.org/10.7554/eLife.82729
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