Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy

Henkel, Nicholas D.; Smail, Marissa A.; Wu, Xiaojun; Enright, Heather A.; Fischer, Nicholas O.; Eby, Hunter M.; McCullumsmith, Robert E.; Shukla, Rammohan

doi:10.1038/s41598-021-98534-3

Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy

Journal Article · Mon Sep 27 00:00:00 UTC 2021 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-021-98534-3· OSTI ID:1843129

Henkel, Nicholas D. ^[1]; Smail, Marissa A. ^[2]; Wu, Xiaojun ^[1]; Enright, Heather A. ^[3]; Fischer, Nicholas O. ^[3]; Eby, Hunter M. ^[1]; McCullumsmith, Robert E. ^[4]; Shukla, Rammohan ^[1]

Univ. of Toledo, OH (United States)
Univ. of Cincinnati, OH (United States)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Univ. of Toledo, OH (United States); ProMedica, Toledo, OH (United States)

Animal models have expanded our understanding of temporal lobe epilepsy (TLE). However, translating these to cell-specific druggable hypotheses is not explored. Herein, we conducted an integrative insilico-analysis of an available transcriptomics dataset obtained from animals with pilocarpine-induced-TLE. A set of 119 genes with subtle-to-moderate impact predicted most forms of epilepsy with ~ 97% accuracy and characteristically mapped to upregulated homeostatic and downregulated synaptic pathways. The deconvolution of cellular proportions revealed opposing changes in diverse cell types. The proportion of nonneuronal cells increased whereas that of interneurons, except for those expressing vasoactive intestinal peptide (Vip), decreased, and pyramidal neurons of the cornu-ammonis (CA) subfields showed the highest variation in proportion. A probabilistic Bayesian-network demonstrated an aberrant and oscillating physiological interaction between nonneuronal cells involved in the blood–brain-barrier and Vip interneurons in driving seizures, and their role was evaluated insilico using transcriptomic changes induced by valproic-acid, which showed opposing effects in the two cell-types. Additionally, we revealed novel epileptic and antiepileptic mechanisms and predicted drugs using causal inference, outperforming the present drug repurposing approaches. These well-powered findings not only expand the understanding of TLE and seizure oscillation, but also provide predictive biomarkers of epilepsy, cellular and causal micro-circuitry changes associated with it, and a drug-discovery method focusing on these events.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: NIH; USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1843129

Report Number(s):: LLNL-JRNL-829057; 1044712

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 11; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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