MicroRNAs as regulators of brain function and targets for treatment of epilepsy

Abstract

Seizures result from hypersynchronous, abnormal firing of neuronal populations and are the primary clinical symptom of the epilepsies. Brain tissue from animal models and patients with acquired forms of epilepsy commonly features selective neuronal loss, gliosis, inflammatory markers and microscopic and macroscopic reorganization of networks. The gene expression landscape is a critical driver of these changes, and gene expression is fine tuned by small, non-coding RNAs called microRNAs (miRNAs). miRNAs inhibit the function of protein-coding transcripts, resulting in changes in multiple aspects of cell structure and function, including axonal and dendritic structure and the repertoire of neurotransmitter receptors, ion channels and transporters that establish neurophysiological functions. Dysregulation of the miRNA system has emerged as a mechanism that underlies epileptogenesis. Given that miRNAs can act on multiple mRNA targets, their manipulation offers a novel, multi-targeting approach to correct disturbed gene expression patterns. Targeting of some miRNAs has also been used to selectively upregulate individual transcripts, offering the possibility of precision therapy approaches for disorders of haploinsufficiency. In this Review, we discuss how miRNAs determine and control neuronal and glial functions, how this process is altered in states associated with hyperexcitability, and the prospects for miRNA targeting for the treatment of epilepsy.

Key points

  • Small non-coding RNAs known as microRNAs (miRNAs) are critical regulators of brain development and brain function.

  • Expression of miRNAs differs between cell types; in neurons, miRNA function responds to and shapes neuronal activity.

  • Epilepsy-inciting events, such as traumatic brain injury, cerebrovascular insults and status epilepticus, alter the expression and/or function of miRNAs, which could contribute to the pathogenesis of epilepsy.

  • In vivo targeting of miRNAs in animal models has identified several miRNAs that have functional roles in epilepsy.

  • Targeting of miRNAs is a potential strategy for the treatment and prevention of epilepsy, but challenges in the delivery and safety of therapeutics remain to be overcome.

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Fig. 1: MicroRNA nomenclature.
Fig. 2: Epilepsy-related signalling pathways that are regulated by microRNAs in neurons and glia.
Fig. 3: Activity-dependent localized microRNA maturation in neurons.

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Acknowledgements

The authors thank the following funding agencies for support: Science Foundation Ireland (SFI) under grant number 16/RC/3948, co-funded under the European Regional Development Fund and by FutureNeuro industry partners; SFI awards 13/IA/1891, 11/TIDA/B1988, 18/SIRG/5646; the Health Research Board Ireland (HRA-POR-2013–325); the Irish Research Council; the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement number 602130; and H2020 Marie S Curie Individual Fellowship (EpimiRGen). The authors also thank their many colleagues.

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G.P.B. researched data for this article. Both authors made substantial contributions to discussion of the content, wrote the manuscript and reviewed and/or edited the manuscript before submission.

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Correspondence to David C. Henshall.

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D.C.H. is an inventor on US patent no. US 9,803,200 B2, “Inhibition of microRNA-134 for the treatment of seizure-related disorders and neurologic injuries”. G.P.B. declares no competing interests.

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Glossary

Processing bodies

Ribonucleoprotein aggregates found in the cytoplasm that are composed of translationally repressed mRNAs and proteins that are involved in mRNA decay.

Synaptic scaling

A form of compensatory neuroplasticity in which neurons respond to persistently high activity by reducing synaptic strength to restore activity to within the normal dynamic range.

miRNA sponge

A nucleotide construct made up of repeats of sequences that are complementary to microRNA and that consequently binds and/or absorbs any available microRNA.

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Brennan, G.P., Henshall, D.C. MicroRNAs as regulators of brain function and targets for treatment of epilepsy. Nat Rev Neurol (2020). https://doi.org/10.1038/s41582-020-0369-8

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