Detecting and defining drug-induced seizures: the power of functional imaging in the larval zebrafish brain

Seizures can be defined as rhythmic and synchronous abnormal central nervous system (CNS) activity and are complex neurological processes that require in vivo models, with intact CNS architecture, for a full mechanistic understanding. There are many causes of seizures including as an unwanted side effect of some drugs, most commonly occurring as a result of pharmacological modulation of certain risk-associated mechanisms. Historically, the standard approach for assessing new drug seizure liability was the rodent electroencephalogram (EEG), but this methodology is highly invasive, complex, expensive, and has high compound requirements; these factors mean it is often applied late in drug development. Consequently more rapid, cost effective and 3Rs friendly methods are needed, which can be deployed earlier in drug development. We have recently developed an imaging-based approach, using 4 day old transgenic zebrafish, in which we can non-invasively quantify drug-induced neural activity across the whole brain (akin to functional MRI), and have begun to probe this system with multiple representative drugs activating a range of mechanisms strongly associated with the induction of seizures in mammals. From these studies we have demonstrated that mechanism-specific patterns of brain activity arise from treatment with different classes of drug, and that specific brain regions appear to be relatively consistently activated by compounds strongly associated with seizurogenesis, compared with those known to be free of this activity. This methodology thus affords a new approach for the identification of seizure liability amongst drugs under early development. Crucially, compared with any other approach including EEG, this methodology also provides detailed information that can reveal the underlying pharmacological mechanism behind a compound’s CNS activity and, as such, has far reaching potential applications beyond just the detection of drug-induced seizures for the purposes of drug discovery and development.