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

Abstract 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 pilocarpi...

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Autores principales:	Nicholas D. Henkel, Marissa A. Smail, Xiaojun Wu, Heather A. Enright, Nicholas O. Fischer, Hunter M. Eby, Robert E. McCullumsmith, Rammohan Shukla
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/96f33045d9774ed79f416b8982c1c3dd
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spelling	oai:doaj.org-article:96f33045d9774ed79f416b8982c1c3dd2021-12-02T17:37:34ZCellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy10.1038/s41598-021-98534-32045-2322https://doaj.org/article/96f33045d9774ed79f416b8982c1c3dd2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98534-3https://doaj.org/toc/2045-2322Abstract 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.Nicholas D. HenkelMarissa A. SmailXiaojun WuHeather A. EnrightNicholas O. FischerHunter M. EbyRobert E. McCullumsmithRammohan ShuklaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nicholas D. Henkel Marissa A. Smail Xiaojun Wu Heather A. Enright Nicholas O. Fischer Hunter M. Eby Robert E. McCullumsmith Rammohan Shukla Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy
description	Abstract 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.
format	article
author	Nicholas D. Henkel Marissa A. Smail Xiaojun Wu Heather A. Enright Nicholas O. Fischer Hunter M. Eby Robert E. McCullumsmith Rammohan Shukla
author_facet	Nicholas D. Henkel Marissa A. Smail Xiaojun Wu Heather A. Enright Nicholas O. Fischer Hunter M. Eby Robert E. McCullumsmith Rammohan Shukla
author_sort	Nicholas D. Henkel
title	Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy
title_short	Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy
title_full	Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy
title_fullStr	Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy
title_full_unstemmed	Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy
title_sort	cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/96f33045d9774ed79f416b8982c1c3dd
work_keys_str_mv	AT nicholasdhenkel cellularmolecularandtherapeuticcharacterizationofpilocarpineinducedtemporallobeepilepsy AT marissaasmail cellularmolecularandtherapeuticcharacterizationofpilocarpineinducedtemporallobeepilepsy AT xiaojunwu cellularmolecularandtherapeuticcharacterizationofpilocarpineinducedtemporallobeepilepsy AT heatheraenright cellularmolecularandtherapeuticcharacterizationofpilocarpineinducedtemporallobeepilepsy AT nicholasofischer cellularmolecularandtherapeuticcharacterizationofpilocarpineinducedtemporallobeepilepsy AT huntermeby cellularmolecularandtherapeuticcharacterizationofpilocarpineinducedtemporallobeepilepsy AT robertemccullumsmith cellularmolecularandtherapeuticcharacterizationofpilocarpineinducedtemporallobeepilepsy AT rammohanshukla cellularmolecularandtherapeuticcharacterizationofpilocarpineinducedtemporallobeepilepsy
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Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy

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