MicroRNA-218 instructs proper assembly of hippocampal networks
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eLife assessment
This fundamental study addresses the role of miRNA-218 in circuit development, seizure susceptibility, and behavior. The supporting experimental evidence provided by the authors is solid, although more mechanistic insight into how miRNA-218 controls neuronal cell type function during circuit development to then impact seizures and behavior would have strengthened the study. This work has broad implications for researchers working on the role of neuronal microRNA in neurodevelopmental and neurological diseases.
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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.
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eLife assessment
This fundamental study addresses the role of miRNA-218 in circuit development, seizure susceptibility, and behavior. The supporting experimental evidence provided by the authors is solid, although more mechanistic insight into how miRNA-218 controls neuronal cell type function during circuit development to then impact seizures and behavior would have strengthened the study. This work has broad implications for researchers working on the role of neuronal microRNA in neurodevelopmental and neurological diseases.
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Reviewer #1 (Public Review):
In this paper, the authors tried to elucidate specific neuronal microRNAs which play an important role in the assembly of hippocampal networks. Using expression screening, they narrowed down on the microRNA miR-218, which is abundantly expressed at early postnatal stages of hippocampal development. Using different loss-of-function tools (antisense oligonucleotides, conditional microRNA knockout mice), they found that miR-218 inhibition early in life leads to a higher susceptibility of mice to develop epileptic seizures, as well as subtle behavioural alterations. These phenotypes were accompanied by disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. An important role for miR-218 specifically in GABAergic interneurons is …
Reviewer #1 (Public Review):
In this paper, the authors tried to elucidate specific neuronal microRNAs which play an important role in the assembly of hippocampal networks. Using expression screening, they narrowed down on the microRNA miR-218, which is abundantly expressed at early postnatal stages of hippocampal development. Using different loss-of-function tools (antisense oligonucleotides, conditional microRNA knockout mice), they found that miR-218 inhibition early in life leads to a higher susceptibility of mice to develop epileptic seizures, as well as subtle behavioural alterations. These phenotypes were accompanied by disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. An important role for miR-218 specifically in GABAergic interneurons is supported by the use of mice with an interneuron-specific loss of miR-218. However, the authors do not directly address which of the cellular phenotypes is causally involved in seizure susceptibility and behavioural alterations. Moreover, the authors describe molecular changes in interneurons and pyramidal neurons which are resulting from miR-218 inhibition in the mouse hippocampus. However, the identity of molecular pathways downstream of miR-218 in the context of epileptic seizures and behaviour remains unexplored.
Altogether, this study has a potentially high impact on the field of neuronal microRNA research and more specifically neuronal circuit assembly. The methods will be of high relevance for the microRNA community studying microRNA function in the context of early neural circuit development in mice in vivo. From a clinical point of view, these results could also increase our knowledge about the mechanisms of epileptic seizure development.
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Reviewer #2 (Public Review):
The current study by Taylor and colleagues investigated the role of microRNA-218 in hippocampal development and discover that disturbances in miR-218 during a key developmental window can lead to persistent changes in network excitability which could have implications for neurodevelopmental and neurological diseases. They found that miR-218 is developmentally regulated in the mouse hippocampus and resides in both excitatory pyramidal neurons and interneurons. Using antagomirs (inhibitors) specifically targeted to miR-218 they find that persistent inhibition of miR-218 elevates network activity and renders mice more susceptible to seizures when challenged with a chemoconvulsant. Additionally antagomir treated mice displayed altered cognitive processing when compared to control-treated mice. Taylor and …
Reviewer #2 (Public Review):
The current study by Taylor and colleagues investigated the role of microRNA-218 in hippocampal development and discover that disturbances in miR-218 during a key developmental window can lead to persistent changes in network excitability which could have implications for neurodevelopmental and neurological diseases. They found that miR-218 is developmentally regulated in the mouse hippocampus and resides in both excitatory pyramidal neurons and interneurons. Using antagomirs (inhibitors) specifically targeted to miR-218 they find that persistent inhibition of miR-218 elevates network activity and renders mice more susceptible to seizures when challenged with a chemoconvulsant. Additionally antagomir treated mice displayed altered cognitive processing when compared to control-treated mice. Taylor and colleagues then identified potential pathways and targets through which miR-218 may exert control over network formation and stabilisation and identified cell-type-specific targets through which it may function. Overall they find that the activity of miR-218 and its effects on network development may be mediated through its activity in interneurons.
The conclusions of this paper are mostly excellently supported by extensive and advanced experimentation.
The data on miR-218 is the least convincing element of the paper but there are inherent difficulties in assessing miR-mediated targeting which the authors may have encountered. Firstly the justification for performing gene ontology on genes with an FC of greater than 0 must be included. Similarly, the use of p values of less than 0.2 lacks stringency and authors should specify why these parameters were chosen. Otherwise, the gene ontology data is difficult to interpret. Protein data may add to this section also.
The authors state they do not analyse known developmental miRs such as miR-124. But the reasoning behind this is not explained. As known developmental miRNAs, analysing their expression would add confidence to the data. Furthermore, the statistical significance of Fig 1B is unclear.
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