An alternative approach for assessing drug-induced seizures, using non-protected larval zebrafish

Seizures are the result of abnormal brain activity and can have many causes including as an unwanted side effect of new drugs. To test for this during drug development, pharmaceutical companies traditionally measure brain electrical activity in drug-exposed rats and mice using the electroencephalogram or EEG. This approach is invasive, slow and expensive. Consequently new methods are needed that reduce animal suffering and which are more amenable to providing earlier warning flags during the drug development process.

In an exciting development, we have recently established a novel imaging-based approach, using a non-protected life stage (4 days old, circa. 3mm in length) of a transgenic zebrafish, in which we can non-invasively measure drug-induced activity across the whole brain .These larval zebrafish express a fluorescent molecule in all neurons of the nervous system which allows visualization of electrical activity using advanced fluorescent microscopy. We have begun to demonstrate that different types of drug generate different patterns of activity giving this project a very strong start. The successful student will build on these findings to generate neural activity data for a broad range of pharmacological mechanisms that produce seizures and (s)he will address the following three main objectives of the project:


1) Test the hypothesis that patterns of neural activity in the brain are linked to specific types of drug. This will generate a reference set of brain activity maps for subsequently identifying seizures, and the mechanisms causing these seizures, in new drugs;


2) Establish why certain types of drug result in altered behaviour, whereas others do not, by comparing existing larval zebrafish behavioral data (e.g. Winter et al., 2008) with imaging data from drug-exposed larvae. This will also provide data for identifying neural activity patterns (and associated behavioral phenotypes) in zebrafish that may represent equivalents of certain classes of seizure/convulsion in mammals;

3) To define the relationship between the non-invasive imaging data, and direct measurement of electrical activity via EEG in 4 day old larval zebrafish. This will allow confirmation of the electrical basis of observed brain activity maps and help translation between the responses of zebrafish and more established (mammalian) seizure models.
This project has huge potential to refine the assessment of new drug seizure liability and replace the use of protected with non-protected animals for this purpose. In addition, the general approach used here has many applications in neuroscience beyond the detection of drug-induced seizure.