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)
-
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.
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).
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.
Metrics
-
- 1,131
- views
-
- 176
- downloads
-
- 5
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
MicroRNA-218 instructs proper assembly of hippocampal networks
eLife 12:e82729.
https://doi.org/10.7554/eLife.82729
Further reading
-
- Neuroscience
Time estimation is an essential prerequisite underlying various cognitive functions. Previous studies identified ‘sequential firing’ and ‘activity ramps’ as the primary neuron activity patterns in the medial frontal cortex (mPFC) that could convey information regarding time. However, the relationship between these patterns and the timing behavior has not been fully understood. In this study, we utilized in vivo calcium imaging of mPFC in rats performing a timing task. We observed cells that showed selective activation at trial start, end, or during the timing interval. By aligning long-term time-lapse datasets, we discovered that sequential patterns of time coding were stable over weeks, while cells coding for trial start or end showed constant dynamism. Furthermore, with a novel behavior design that allowed the animal to determine individual trial interval, we were able to demonstrate that real-time adjustment in the sequence procession speed closely tracked the trial-to-trial interval variations. And errors in the rats’ timing behavior can be primarily attributed to the premature ending of the time sequence. Together, our data suggest that sequential activity maybe a stable neural substrate that represents time under physiological conditions. Furthermore, our results imply the existence of a unique cell type in the mPFC that participates in the time-related sequences. Future characterization of this cell type could provide important insights in the neural mechanism of timing and related cognitive functions.
-
- Neuroscience
Granule cells of the cerebellum make up to 175,000 excitatory synapses on a single Purkinje cell, encoding the wide variety of information from the mossy fibre inputs into the cerebellar cortex. The granule cell axon is made of an ascending portion and a long parallel fibre extending at right angles, an architecture suggesting that synapses formed by the two segments of the axon could encode different information. There are controversial indications that ascending axon (AA) and parallel fibre (PF) synapse properties and modalities of plasticity are different. We tested the hypothesis that AA and PF synapses encode different information, and that the association of these distinct inputs to Purkinje cells might be relevant to the circuit and trigger plasticity, similar to the coincident activation of PF and climbing fibre inputs. Here, by recording synaptic currents in Purkinje cells from either proximal or distal granule cells (mostly AA and PF synapses, respectively), we describe a new form of associative plasticity between these two distinct granule cell inputs. We show for the first time that synchronous AA and PF repetitive train stimulation, with inhibition intact, triggers long-term potentiation (LTP) at AA synapses specifically. Furthermore, the timing of the presentation of the two inputs controls the outcome of plasticity and induction requires NMDAR and mGluR1 activation. The long length of the PFs allows us to preferentially activate the two inputs independently, and despite a lack of morphological reconstruction of the connections, these observations reinforce the suggestion that AA and PF synapses have different coding capabilities and plasticity that is associative, enabling effective association of information transmitted via granule cells.
