New Insights Shed Light on Epilepsy and Autism Spectrum Disorders
Article Summary
- Miller School researchers published a study that found KCNQ genes regulate gamma-aminobutyric acid (GABA) release from neural cells.
- Genetic mutations can limit GABA release and contribute to neuron excitability associated with epilepsy and autism spectrum disorder.
- The study showed for the first time how KCNQ variations in glia affect GABA release.
Researchers at the University of Miami Miller School of Medicine have shown that the potassium channel gene KCNQ is active in neural cells called glia. KCNQ mutations can profoundly affect both neurons and glia.
The research team also showed that genetic variations limit the glia’s ability to release the gamma-aminobutyric acid (GABA) neurotransmitter, driving the neuronal hyperexcitability associated with certain forms of epilepsy and autism spectrum disorder (ASD).
The study was published in the journal Neuron.
“We started investigating the function of KCNQ channels in glia and we found it is necessary to release GABA,” said Laura Bianchi, Ph.D., associate professor of physiology and biophysics at the Miller School and senior author on the study. “Reduced GABA led to the hyperexcitable neurons that have been linked to self-limited neonatal epilepsy, developmental and epileptic encephalopathy and ASD.”
KCNQ’s Double Life
Dr. Bianchi and her research team, including first author Bianca Graziano, M.D., found that KCNQ leads a double life. In neurons, the gene expresses channel proteins that allow potassium out of cells to control excitability. KCNQ variations can make these channels malfunction, leading to neuronal hyperexcitability and disease.
Prior to this study, few researchers had addressed the impact of KCNQ mutations on glia, which serve as caretaker cells in the brain by supporting neuronal function. One of their tasks is releasing GABA, which inhibits neuronal excitability.
“This causes a similar result from two completely separate mechanisms,” said Dr. Bianchi. “If neurons lose KCNQ, they become more excitable. If glia lose KCNQ, they lose the ability to release inhibitory GABA and consequently neurons become more excitable. It’s the same result from different pathways.”
Showing the Impact of KCNQ Variations
The team studied kqt-2, the KCNQ channels found in tiny C. elegans roundworms, as well as human channels expressed in the worms using in vivo calcium, voltage and GABA imaging and behavioral studies. Their work showed for the first time how KCNQ variations in glia affect GABA release.
Ultimately, the study provides important insights into how KCNQ impacts neurons. Now researchers can work to target KCNQ pathways in glia to potentially dampen neuronal excitability.
“If KCNQ channels in glia are this important to express the disease phenotype, then we can try to target those glial channels instead of the neuronal ones,” said Dr. Bianchi. “Just gaining this fundamental knowledge and understanding that these gene variations are expressed in both neurons and glia opens up additional options to target more than one cell type to help alleviate these conditions.”