Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy.
Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy.
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DOI：
10.1038/s41598-021-98534-3
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发表时间：
2021-09-27
影响因子：
4.6
通讯作者：
Shukla R
中科院分区：
文献类型：
--
作者：
Henkel ND;Smail MA;Wu X;Enright HA;Fischer NO;Eby HM;McCullumsmith RE;Shukla R
动物模型扩大了我们对颞叶癫痫(TLE)的认识。然而，将这些转化为特定于细胞的可用药假说并未得到探索。在这里，我们对从匹罗卡品诱导的TLE动物中获得的可用的转录组学数据集进行了综合的信息分析。一组具有轻微到中等影响的119个基因预测了大多数形式的癫痫， ~ 的准确率为97%，并特征地映射到上调的内稳态和下调的突触通路。细胞比例的反卷积显示了不同细胞类型的相反变化。除表达血管活性肠肽(VIP)的细胞外，非神经细胞所占比例增加，中间神经元所占比例减少，且以山角(CA)亚区锥体细胞比例变化最大。概率贝叶斯网络显示了参与血脑屏障的非神经细胞和VIP中间神经元在驱动癫痫发作中的异常和振荡的生理相互作用，并利用丙戊酸诱导的转录变化来评估它们的作用，这在两种细胞类型中显示出相反的作用。此外，我们揭示了新的癫痫和抗癫痫机制，并使用因果推断预测药物，表现优于目前的药物再利用方法。这些有力的发现不仅扩大了对TLE和癫痫振荡的理解，还提供了癫痫的预测性生物标志物、与之相关的细胞和因果微电路变化，以及专注于这些事件的药物发现方法。
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.
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影响因子：
4.6
作者：
Agrahari R;Foroushani A;Docking TR;Chang L;Duns G;Hudoba M;Karsan A;Zare H
通讯作者：
Zare H
影响因子：
14.9
作者：
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影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
9.3
作者：
Baron M;Veres A;Wolock SL;Faust AL;Gaujoux R;Vetere A;Ryu JH;Wagner BK;Shen-Orr SS;Klein AM;Melton DA;Yanai I
通讯作者：
Yanai I
影响因子：
9.9
作者：
CEREGHINO, JJ;BROCK, JT;WHITE, BG
通讯作者：
WHITE, BG