Several years ago, a mutant fruit fly was discovered in the lab of Troy Littleton, Menicon Professor in Neuroscience at MIT's Picower Institute for Learning and Memory. The fly mutant, called zydeco, gets seizures because of excessive activity in neurons due to stress, similarly to epilepsy patients. Researchers have since been working to learn more about how the fruit fly mutation leads to seizures. They have learned more about the sequence of molecular events that leads to seizures, which can open up new potential treatment avenues.
The scientists knew that the zydeco mutation specifically impacts glial cells - neuronal supporters - in the brain's cortex. The protein encoded by zydeco is an exchanger that pumps calcium ions out of cortical glial cells. Maintaining ion balances is essential for neurons, whose activity depends on the movement of ions in and out of cells. Neurons take up sodium ions so they can activate, and release potassium ions to calm down. If there is too much potassium outside of the neuronal cell, it becomes hard for the neuron to get rid of it and relax. The researchers wanted to know why a defect in the movement of calcium ions could cause neurons nearby to become overly active under stresses like movement or fever.
Reporting in eLife after four years of study, the researchers determined that when there’s too much calcium in cortical glial cells, they overstimulate a cellular pathway, causing the removal of many potassium channels that get potassium ions away from neurons. The resulting excess potassium means neurons are unable to relax when they’re excited, leading to seizures.
"No one has really shown how calcium signaling in glia could directly communicate with this more classical role of glial cells in potassium buffering," Littleton said. "So this is a really important discovery linking an observation that's been found in glia for a long time - these calcium oscillations that no one really understood - to a real biological function in glial cells where it's contributing to their ability to regulate ionic balance around neurons."
The zydeco mutants can be seen in this video from the Littleton lab.
As postdoctoral researcher Shirley Weiss learned more about the sequence of molecular events, more targets for therapeutic intervention were identified. She performed an analysis of genes that might be related to seizures when there is an excess of calcium. After assessing 847 genes, she found 50 that could impact seizures. One had a close connection to calcium level regulation and is also expressed in cortical glial cells - calcineurin. Inhibition of calcineurin stopped seizures in the zydeco mutants.
Additional work revealed that if calcineurin is hyperactivated in zydeco mutants, a process called endocytosis is encouraged in glial cells, and too much of a glial potassium channel called Sandman was absorbed into the cell. Because Sandman was lost from the cell membrane, potassium was not being removed from around the glia. By suppressing endocytosis in the zydeco mutants, seizures were reduced - Sandman was able to remove enough potassium.
The researchers noted that drug developers aiming to treat seizures might benefit from targeting glial pathways. Around the world, about 60 million people are affectedly epilepsy. This work may help them, as well as providing insight into neurobiology.
Learn how to deal with a tonic-clonic seizure from the video.
Sources: AAAS/Eurekalert! via Picower at MIT, Journal of Neuroscience, eLife