Cellular, molecular, and therapeutic characterization of pilocarpine

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.

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Fig: Distinct transcriptomics and pathway profiles of pilocarpine induced TLE in mice. (A) Principal components analysis segregating the transcriptomics profile of the control and pilocarpine induced TLE mice. (B) Frequency of differentially expressed genes binned based on log-fold changes across down- (blue) and up- (yellow) regulated genes. See Table for genes under each bin. (C) Pathway profiles of up- and downregulated genes by log-fold change bin (from B) using Gene Ontology. The − log10(q value) of each pathway was used to plot the heatmap. The lighter-to-darker shades of blue and yellow indicate increasing significance of down- and upregulated pathways, respectively. See Table for the pathways grouped under each theme.

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.

Henkel, N.D., Smail, M.A., Wu, X. et al. Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy. Sci Rep 11, 19102 (2021). https://doi.org/10.1038/s41598-021-98534-3

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