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MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control

Heiland, Mona; Connolly, Niamh MC; Mamad, Omar; Nguyen, Ngoc T; Kesavan, Jaideep C; Langa, Elena; Fanning, Kevin; ... Henshall, David C; + view all (2023) MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control. Proceedings of the National Academy of Sciences (PNAS) , 120 (30) , Article e2216658120. 10.1073/pnas.2216658120. Green open access

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Abstract

There remains an urgent need for new therapies for treatment-resistant epilepsy. Sodium channel blockers are effective for seizure control in common forms of epilepsy, but loss of sodium channel function underlies some genetic forms of epilepsy. Approaches that provide bidirectional control of sodium channel expression are needed. MicroRNAs (miRNA) are small noncoding RNAs which negatively regulate gene expression. Here we show that genome-wide miRNA screening of hippocampal tissue from a rat epilepsy model, mice treated with the antiseizure medicine cannabidiol, and plasma from patients with treatment-resistant epilepsy, converge on a single target-miR-335-5p. Pathway analysis on predicted and validated miR-335-5p targets identified multiple voltage-gated sodium channels (VGSCs). Intracerebroventricular injection of antisense oligonucleotides against miR-335-5p resulted in upregulation of Scn1a, Scn2a, and Scn3a in the mouse brain and an increased action potential rising phase and greater excitability of hippocampal pyramidal neurons in brain slice recordings, consistent with VGSCs as functional targets of miR-335-5p. Blocking miR-335-5p also increased voltage-gated sodium currents and SCN1A, SCN2A, and SCN3A expression in human induced pluripotent stem cell-derived neurons. Inhibition of miR-335-5p increased susceptibility to tonic-clonic seizures in the pentylenetetrazol seizure model, whereas adeno-associated virus 9-mediated overexpression of miR-335-5p reduced seizure severity and improved survival. These studies suggest modulation of miR-335-5p may be a means to regulate VGSCs and affect neuronal excitability and seizures. Changes to miR-335-5p may reflect compensatory mechanisms to control excitability and could provide biomarker or therapeutic strategies for different types of treatment-resistant epilepsy.

Type: Article
Title: MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.2216658120
Publisher version: https://doi.org/10.1073/pnas.2216658120
Language: English
Additional information: Copyright © 2023 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Keywords: Adeno-associated virus, antisense oligonucleotides, drug resistance, epilepsy, noncoding RNA, Humans, Mice, Rats, Animals, Induced Pluripotent Stem Cells, Seizures, Epilepsy, MicroRNAs, Voltage-Gated Sodium Channels, NAV1.1 Voltage-Gated Sodium Channel, NAV1.3 Voltage-Gated Sodium Channel
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10173985
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