MicroRNA targeting of the P2X7 purinoceptor opposes a contralateral epileptogenic focus in the hippocampus

Title: MicroRNA targeting of the P2X7 purinoceptor opposes a contralateral epileptogenic focus in the hippocampus
Authors: Jimenez-Mateos, Eva M.
Arribas-Blazquez, Marina
Sanz-Rodriguez, Amaya
Mooney, Catherine
Permanent link: http://hdl.handle.net/10197/10066
Date: 3-Dec-2015
Online since: 2019-04-23T09:12:28Z
Abstract: The ATP-gated ionotropic P2X7 receptor (P2X7R) modulates glial activation, cytokine production and neurotransmitter release following brain injury. Levels of the P2X7R are increased in experimental and human epilepsy but the mechanisms controlling P2X7R expression remain poorly understood. Here we investigated P2X7R responses after focal-onset status epilepticus in mice, comparing changes in the damaged, ipsilateral hippocampus to the spared, contralateral hippocampus. P2X7Rgated inward currents were suppressed in the contralateral hippocampus and P2rx7 mRNA was selectively uploaded into the RNA-induced silencing complex (RISC), suggesting microRNA targeting. Analysis of RISC-loaded microRNAs using a high-throughput platform, as well as functional assays, suggested the P2X7R is a target of microRNA-22. Inhibition of microRNA-22 increased P2X7R expression and cytokine levels in the contralateral hippocampus after status epilepticus and resulted in more frequent spontaneous seizures in mice. The major pro-inflammatory and hyperexcitability effects of microRNA-22 silencing were prevented in P2rx7-/-mice or by treatment with a specific P2X7R antagonist. Finally, in vivo injection of microRNA-22 mimics transiently suppressed spontaneous seizures in mice. The present study supports a role for post-transcriptional regulation of the P2X7R and suggests therapeutic targeting of microRNA-22 may prevent inflammation and development of a secondary epileptogenic focus in the brain.
Funding Details: European Commission - European Regional Development Fund
European Commission - Seventh Framework Programme (FP7)
Health Research Board
Irish Research Council
Science Foundation Ireland
Type of material: Journal Article
Publisher: Springer
Journal: Scientific Reports
Volume: 5
Issue: 17486
Copyright (published version): 2015 the Authors
Keywords: Brain injuryEpilepsyATP-gated ionotropic P2X7 receptorMicroRNA targetingStatus epilepticusEpileptogenic
DOI: 10.1038/srep17486
Language: en
Status of Item: Peer reviewed
Appears in Collections:Computer Science Research Collection

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