Biofluid-specific variations in circulating 5' transfer RNA fragments during ictal and interictal states in experimental temporal lobe epilepsy

Objective: Circulating small noncoding RNAs represent potential biomarkers of temporal lobe epilepsy (TLE). Recently, two transfer RNA fragments (tRFs), 5'tRF Glu-CTC and Gly-GCC, were found to be elevated in plasma samples collected in advance of a seizure in TLE patients, suggesting they may serve as potential wet biomarkers of seizure risk or occurrence. The optimal biofluid source for tRF assay, species conservation, and whether their levels reflect specific ictal or interictal states remain uncertain. Methods: Here, we analyzed the longitudinal dynamics of 5'tRF Glu-CTC and Gly-GCC in both cerebrospinal fluid (CSF) and plasma in the pilocarpine model of TLE in rats. We sampled CSF and plasma across multiple time points during the chronic phase of TLE, while performing continuous electroencephalographic monitoring to correlate 5'tRFs levels with electrophysiological activity. Results: Levels of both 5'tRFs were significantly higher in plasma but not in CSF in epileptic rats compared to controls. Plasma levels of both did not, however, correlate with seizure frequency. In contrast, 5'tRF Gly-GCC levels in CSF correlated with interictal spike activity, whereas plasma levels again did not show a dynamic response. Consistent with these findings, we observed higher levels of 5'tRFs in plasma but not in CSF samples from human TLE patients as compared with healthy controls. Significance: These data suggest that 5'tRFs accumulate in the brain during interictal spike activity and accumulate in the plasma of individuals with epilepsy. 5'tRFs may therefore serve as accessible, diagnostic biomarkers for epilepsy.