Eimon Peter M, Ghannad-Rezaie Mostafa, De Rienzo Gianluca, Allalou Amin, Wu Yuelong, Gao Mu, Roy Ambrish, Skolnick Jeffrey, Yanik Mehmet Fatih
Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
UZH/ETH Irchel Campus, Y17-L76, Winterthurerstrasse 190, 8057, Zürich, Switzerland.
Nat Commun. 2018 Jan 15;9(1):219. doi: 10.1038/s41467-017-02404-4.
Neurological drugs are often associated with serious side effects, yet drug screens typically focus only on efficacy. We demonstrate a novel paradigm utilizing high-throughput in vivo electrophysiology and brain activity patterns (BAPs). A platform with high sensitivity records local field potentials (LFPs) simultaneously from many zebrafish larvae over extended periods. We show that BAPs from larvae experiencing epileptic seizures or drug-induced side effects have substantially reduced complexity (entropy), similar to reduced LFP complexity observed in Parkinson's disease. To determine whether drugs that enhance BAP complexity produces positive outcomes, we used light pulses to trigger seizures in a model of Dravet syndrome, an intractable genetic epilepsy. The highest-ranked compounds identified by BAP analysis exhibit far greater anti-seizure efficacy and fewer side effects during subsequent in-depth behavioral assessment. This high correlation with behavioral outcomes illustrates the power of brain activity pattern-based screens and identifies novel therapeutic candidates with minimal side effects.
神经药物常常伴有严重的副作用，但药物筛选通常只关注疗效。我们展示了一种利用高通量体内电生理学和脑活动模式（BAPs）的新范式。一个具有高灵敏度的平台可以在很长一段时间内同时记录许多斑马鱼幼体的局部场电位（LFPs）。我们发现，经历癫痫发作或药物诱导副作用的幼体的BAPs复杂性（熵）大幅降低，这与帕金森病中观察到的LFP复杂性降低类似。为了确定增强BAP复杂性的药物是否能产生积极效果，我们在一种难治性遗传性癫痫——德雷维特综合征模型中使用光脉冲触发癫痫发作。通过BAP分析确定的排名最高的化合物在随后的深入行为评估中表现出远更高的抗癫痫疗效和更少的副作用。这种与行为结果的高度相关性说明了基于脑活动模式的筛选的强大作用，并识别出副作用最小的新型治疗候选药物。
