Researchers use optogenetics in fruit flies to prevent later-life seizure-like behavior
Professor Richard Baines and Dr Carlo Giachello have shown that suppressing nervous system activity at a precise stage of embryonic development can prevent seizure-like behavior later in life, using a genetically altered fruit fly model. By expressing an optogenetic protein and exposing the embryo to yellow light at a defined developmental window, the team were able to block the emergence of persistent seizure-like symptoms in adult flies.
Although this work was carried out in Drosophila, the researchers — funded by the Medical Research Council — describe the findings as a proof of principle that early intervention during a sensitive period can alter the course of epilepsy-related phenotypes. They caution that further research in mammalian systems is required before any clinical implications for humans can be drawn.
Professor Baines commented that the underlying biology of central nervous system development shares conserved features across species, which makes the fly a useful model to explore mechanisms that may also be relevant to human epilepsy. Dr Giachello added that optogenetics, the technique they used to control neuronal activity with light, is a rapidly advancing field with potential applications beyond epilepsy research.
Genetic forms of epilepsy in humans often involve gene variants that predispose individuals to develop seizures. In many cases there is a latent phase — the epileptogenic process — during which a previously normal brain undergoes changes that ultimately produce epilepsy. Prior studies show that applying antiepileptic drugs during this latent period can delay seizure onset, but such treatment does not always prevent epilepsy entirely.
The Drosophila study takes a different approach: instead of using drugs, the researchers manipulated neuronal activity directly during a critical embryonic window. They used halorhodopsin, an optogenetic protein that hyperpolarizes (inhibits) neurons when illuminated with yellow light. By turning down excessive neuronal activity when the embryo was roughly 80–90% through development, they found that seizure-like behavior was effectively prevented later in life in their fly models.
Conversely, the team showed that artificially increasing neuronal excitation during the same critical period in otherwise wild-type flies could permanently induce seizure-like behavior and circuit dysfunction. These results indicate the existence of a sensitive period in embryogenesis during which neural activity plays a decisive role in shaping future circuit function and seizure susceptibility.
Lead coauthors on the study included Philsang Hwang and Shih-Wei Chou, with contributing author Zongwei Chen. The research was supported by the Medical Research Council.
Key points
- Manipulating neural activity during a specific embryonic window alters long-term circuit function and seizure susceptibility.
- Suppressing elevated activity during the critical period prevented seizure-like behavior in genetically susceptible flies.
- Increasing excitation during the same period in wild-type flies caused persistent seizure-like phenotypes.
- Early administration of antiepileptic drugs in this model can also rescue induced seizures, suggesting a window for intervention.
Abstract summary
Maturation of neural circuits depends on activity-dependent processes that establish appropriate adult behavior. Disruption of these processes during critical developmental windows may contribute to neurodevelopmental conditions, including epilepsy. Using Drosophila, a model that displays experimental seizure-like activity broadly comparable to clinical phenotypes, the authors identify a sensitive period in embryogenesis. Manipulating activity during this period is sufficient to influence seizure-related behavior at postembryonic stages. Inhibition of elevated activity characteristic of seizure-prone mutants suppresses later seizure behavior, while enhancing excitation in wild-type animals produces persistent seizure-like outcomes and associated synaptic alterations in motoneuron inputs. These induced changes are preventable by prior administration of antiepileptic drugs, highlighting the potential for early interventions to alter the developmental trajectory of genetic epilepsies.
Publication note
The original research, titled “Inappropriate Neural Activity during a Sensitive Period in Embryogenesis Results in Persistent Seizure-like Behavior” by Carlo N.G. Giachello and Richard A. Baines, was published in Current Biology (published online November 5, 2015).