Brain activity patterns in high-throughput electrophysiology screen predict both drug efficacies and side effects

被引：51

作者：

Eimon, Peter M. ^{[1
]}

Ghannad-Rezaie, Mostafa ^{[1
,2
]}

De Rienzo, Gianluca ^{[1
,3
,5
]}

Allalou, Amin ^{[1
]}

Wu, Yuelong ^{[1
]}

Gao, Mu ^{[4
]}

Roy, Ambrish ^{[4
]}

Skolnick, Jeffrey ^{[4
]}

Yanik, Mehmet Fatih ^{[1
,2
]}

机构：

[1] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[2] UZH ETH Irchel Campus, Y17-L76,Winterthurerstr 190, CH-8057 Zurich, Switzerland

[3] Intellimedix, Cambridge, MA 02139 USA

[4] Georgia Inst Technol, 950 Atlantic Dr,Room 2151, Atlanta, GA 30332 USA

[5] Axcella Hlth, 840 Mem Dr, Cambridge, MA 02139 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

HIGHER-ORDER STATISTICS; LOW-DOSE FENFLURAMINE; DRAVET-SYNDROME; SODIUM-CHANNELS; EPILEPSY; SEIZURE; SCN1A; MUTATION; MODEL; SCN2A;

D O I：

10.1038/s41467-017-02404-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

共 78 条

[41] SCN2A encephalopathy A major cause of epilepsy of infancy with migrating focal seizures [J].