AUTHOR=Brindley Elizabeth , Heiland Mona , Mooney Catherine , Diviney Mairead , Mamad Omar , Hill Thomas D. M. , Yan Yan , Venø Morten T. , Reschke Cristina R. , Batool Aasia , Langa Elena , Sanz-Rodriguez Amaya , Heller Janosch P. , Morris Gareth , Conboy Karen , Kjems Jørgen , Brennan Gary P. , Henshall David C. TITLE=Brain cell-specific origin of circulating microRNA biomarkers in experimental temporal lobe epilepsy JOURNAL=Frontiers in Molecular Neuroscience VOLUME=16 YEAR=2023 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2023.1230942 DOI=10.3389/fnmol.2023.1230942 ISSN=1662-5099 ABSTRACT=

The diagnosis of epilepsy is complex and challenging and would benefit from the availability of molecular biomarkers, ideally measurable in a biofluid such as blood. Experimental and human epilepsy are associated with altered brain and blood levels of various microRNAs (miRNAs). Evidence is lacking, however, as to whether any of the circulating pool of miRNAs originates from the brain. To explore the link between circulating miRNAs and the pathophysiology of epilepsy, we first sequenced argonaute 2 (Ago2)-bound miRNAs in plasma samples collected from mice subject to status epilepticus induced by intraamygdala microinjection of kainic acid. This identified time-dependent changes in plasma levels of miRNAs with known neuronal and microglial-cell origins. To explore whether the circulating miRNAs had originated from the brain, we generated mice expressing FLAG-Ago2 in neurons or microglia using tamoxifen-inducible Thy1 or Cx3cr1 promoters, respectively. FLAG immunoprecipitates from the plasma of these mice after seizures contained miRNAs, including let-7i-5p and miR-19b-3p. Taken together, these studies confirm that a portion of the circulating pool of miRNAs in experimental epilepsy originates from the brain, increasing support for miRNAs as mechanistic biomarkers of epilepsy.