Most people with a medical condition called long QT syndrome have a mutation in a gene that causes bouts of fast, chaotic heartbeats. They also experience fainting spells and seizures. The clinical approach has largely assumed that when the heart beats erratically, the brain eventually does not get enough oxygen — which in turn causes the seizures.
Research from Washington University in St. Louis finds that mutations of a gene implicated in long QT syndrome in humans may trigger seizures because of their direct effects on certain classes of neurons in the brain — independent from what the genetic mutations do to heart function. The new work from Arts & Sciences was conducted with fruit flies and is published Aug. 8 in PLOS Genetics.
“This gene seems to be a key factor in the physiological process that protects neurons from starting to fire uncontrollably in response to a rapid increase in temperature, which could lead to paralysis and death,” said Yehuda Ben-Shahar, associate professor of biology in Arts & Sciences.
Alexis Hill, recently a postdoctoral fellow in the Ben-Shahar laboratory, discovered this unexpected relationship as she probed the nervous system response to acute environmental stress.
Heat in general causes neurons to start firing faster, so the brain is particularly sensitive to overheating. Mammals and other large animals have ways to maintain their internal temperature and protect their brains from heat. But not the fruit fly. With no extra bulk in his tiny body, the only thing a fly can do to regulate temperature is to move from an uncomfortable spot to a comfortable one.
Ben-Shahar had previously published work showing flies that lack a gene called sei could not act to save themselves at temperatures above 25 degrees Celsius (77 Fahrenheit). They had no ability to buffer heat stress, and started having seizures as temperatures increased.
In their new work, Hill and Ben-Shahar were able to show that sei protects against heat-induced hyperexcitability only when it is expressed in a few particular classes of neurons and glia. Knocking down the gene in the heart had no effect on seizure activity.This gene sei — named by other researchers who had previously discovered its role in seizure activity — shows up in lots of places in fruit flies: in the neurons responsible for primary communication of both excitatory and inhibitory signals, in the glia cells of the nervous system that support neurons in various ways, and in the heart.
“The ability of flies to resist the heat is in neurons that release neurotransmitters that make other neurons fire faster, the ones that excite neurons,” Ben-Shahar said.