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

(Eimon et al. 2018) In this study, the authors used two Dravet-like zebrafish models, each with a different mutation, to describe a method of monitoring zebrafish larvae via implanted electrodes (as opposed to external EEG-like electrodes) to predict drug efficacy and side effects. This method uses several measurements of brain activity patterns both during and between seizures, and applies complex algorithms to analyze and potentially quantify differences between healthy animals and their mutated siblings.

They found that, in addition to the expected spontaneous seizures, both models of mutated zebrafish larvae had increased seizure-like locomotor activity (movement) when exposed to pulsating light bursts. They then looked at the electrographic signals in the larvae and found that the mutated models had high-amplitude (tall) ictal spikes approximately every 10 minutes, suggesting seizures. These spikes were not found in healthy sibling controls. When they repeated the photic stimulation, they found differences in the spike patterns between mutated zebrafish larvae and healthy controls.

In terms of drug screening, the authors tested over 150 medications, many of which were standard or potentially useful AEDs, on their light-induced locomotor model. Of those, 31 were considered “hits,” in this behavioral screen, representing several different neuronal receptor targets. Most of the medications known to reduce seizures in Dravet syndrome were included in this list of 31 hits. They then performed in-depth analysis of the brain activity patterns of the larvae and compared those analyses to wild-type controls. Six of the 31 hits resulted in brain activity patterns that clustered near that of those of the healthy siblings, which the authors conclude are “true positives” and represent the lowest side effect profiles. Interestingly, the six hits (pargyline, progesterone, promethazine, allopregnanolone, mifepristone, and fluoxeitine) are not traditional medications used to treat DS and were not identified as hits in other zebrafish drug screening models.

Eimon PM, Ghannad-Rezaie M, De Rienzo G, Allalou A, Wu Y, Gao M, Roy A, Skolnick J, Yanik MF. Brain activity patterns in high-throughput electrophysiology screen predict both drug efficacies and side effects. Nat Commun. 2018 Jan 15;9(1):219. doi: 10.1038/s41467-017-02404-4. PubMed PMID: 29335539; PubMed Central PMCID: PMC5768723.
By |2018-02-05T16:45:33+00:00February 5th, 2018|Categories: DSF Research Review|Tags: , |

About the Author:

Nicole is a former scientist and science educator who has an 11 year old son with Dravet syndrome and serves on the Board of Directors for the Dravet Syndrome Foundation. She reviews and summarizes research articles, making the content more accessible to those not involved in the scientific community.