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. P2X7R-gated 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.
Highlights
The Adenosine triphosphate (ATP)-gated ionotropic P2X7 receptor (P2X7R) modulates glial activation, cytokine production and neurotransmitter release following brain injury
Confirming this unilateral feature, analysis of tissue sections stained for Fluoro-Jade B revealed irreversible neuronal death in the ipsilateral but not contralateral hippocampus after status epilepticus (Fig. 1A)
Intra-hippocampal EEG recordings determined that the contralateral hippocampus was recruited during status epilepticus but seizure severity was lower compared to the ipsilateral side (Fig. 1B)
Summary
The ATP-gated ionotropic P2X7 receptor (P2X7R) modulates glial activation, cytokine production and neurotransmitter release following brain injury. MiRNAs are uploaded to the RNA induced silencing complex (RISC) where Argonaute 2 (Ago2) facilitates base-pairing to target mRNAs, resulting in translational repression or degradation of the mRNA25 Both experimental and human TLE are associated with altered expression of miRNA within the seizure focus[26] and recent studies showed that manipulation of miRNAs controlling neuronal microstructure had potent effects on convulsive thresholds[27,28]. It is likely, that miRNAs control other substrates of epileptogenesis such as ion channels and neuroinflammation[2,29,30]. We identify a miRNA targeting the P2X7R in the contralateral hippocampus that functions to suppress neuroinflammatory signaling and epilepsy
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