High Temperatures Suppress Seizures in a Fruit Fly Epilepsy Model
The human brain is an amazing machine powered by electricity. Carefully controlled patterns of changing electrical charges in neurons allow us to to think, move, and speak. When this system is disrupted, very bad things happen. A seizure occurs when a sudden surge of electrical activity in the brain interrupts normal functioning. Seizures are accompanied by various symptoms, including everything from unusual thoughts and uncontrollable movements to a total loss of consciousness. Sometimes seizures have a known cause—a brain injury or drug withdrawal, for example. But often what happens in the brain to cause a seizure is not obvious. Epilepsy is a disease characterized by repeated, unprovoked seizures, and it is a complex condition caused by an intertwining set of genetic and environmental factors. In a recent study published in G3, Arunesh Saras and Mark A. Tanouye untangle a new connection between genetics and temperature in a fruit fly model. They show that even a brief hot shock suppresses seizures in a set of mutants with epilepsy-like phenotypes.
Animal models of complex diseases like epilepsy are crucial because they can be manipulated in the lab and provide a known, controllable genetic background for experimentation. Bang-sensitive Drosophila melanogaster mutants are used as a model system to study seizure disorders. Their name comes from the fact that a mechanical shock or high frequency electrical stimulation easily induces seizure-like activity, including behaviors like paralysis. This trait can be caused by multiple genotypes and some are more sensitive to seizures than others.
In this study, Saras and Tanouye tested the effects of heat shock on bang-sensitive mutants. Surprisingly, they found that even a short exposure to high temperatures suppressed seizures in several different bang-sensitive mutants. After just 30 seconds of heat shock at 38ºC, seizures could not be induced in even the most sensitive mutants genotypes. Unfortunately, this effect doesn’t last long: all of the mutant flies returned to having inducible seizures within an hour. For some genotypes, the effect of heat shock only lasted for around two minutes. The authors used precise electrophysiology recording to confirm that heat shock raised the minimum voltage of electrical stimulation required to induce a seizure in these flies.
Like in epilepsy, the seizures in these experiments are the result of an interaction between genetics and the environment. In fact, the authors initially expected the stress caused by heat shock to make bang-sensitive mutants more susceptible to seizures. But since the exact opposite turned out to be the case, they began investigating possible mechanisms for temperature-dependent seizure suppression. They chose a set of genes already known to be involved in thermoregulation or neuronal activity in D. melanogaster and used RNAi to knockdown their expression in bang-sensitive mutants. None of them had an effect on seizure suppression except for the gene rutabaga (rut), a key enzyme in the cAMP signalling pathway.
The signaling molecule cAMP is an important component of many different physiological processes, including temperature preference behavior in flies. When rut expression was knocked down and cAMP levels decreased, bang-sensitive mutants became susceptible to seizures again even after heat shock. This result was confirmed using a bang-sensitive mutant with a rut knock-out mutation, and electrophysiology recording showed that after heat shock the bang-sensitive rut double mutants required a significantly lower amount of electrical stimulation to trigger a seizure.
These results suggest the protective effect of high temperature works by raising the threshold of electrical activity required to trigger a seizure, and this process is dependent on high levels of cAMP. Though it is still unclear exactly how cAMP interacts with the neuronal processes responsible for seizures, knowing it is involved opens up many new avenues of study. Figuring out how seizures are triggered or suppressed in fruit flies may lead to answers for the millions of humans who struggle with epilepsy.
Saras, A., & Tanouye, M. A. (2016). Seizure Suppression by High Temperature via cAMP Modulation in Drosophila. G3: Genes|Genomes|Genetics, 6(10), 3381-3387. DOI:10.1534/g3.116.034629