Research in mice reveals how the ketogenic diet influences the brain’s activity, offering insights into its therapeutic effects for epilepsy patients.
Sara Moser/WashU Medicine
Ketogenic diets, which are high in fat and very low in carbohydrates, have long been known to reduce epileptic seizures in some patients, but it hasn’t been clear why. A new study by WashU Medicine researchers shows in mice that the diet causes changes in the brain that dampen signaling between cells, opening a potential pathway to targeted therapies.
The ketogenic diet—characterized by high fat intake and minimal carbohydrates—has historically been effective in reducing seizures in some epilepsy sufferers. However, the underlying mechanisms that allow this diet to exert its effects were previously unclear.
Recent research conducted by scientists at Washington University School of Medicine in St. Louis has uncovered that this diet induces significant physical changes in brain cells, influencing their intercellular communication. Specifically, it lessens the intensity of the signals exchanged between neurons. This subdued neural environment may help explain how the ketogenic diet can mitigate the excessive electrical activity associated with epileptic seizures.
This important study is published this month in Cell Reports.
Ghazaleh Ashrafi, PhD, an associate professor in the WashU Medicine Department of Cell Biology & Physiology and the study’s principal investigator, noted that these discoveries open up avenues for new treatment strategies for epilepsy.
“Understanding how the diet operates gives us insight into developing less restrictive interventions that can still control seizures,” Ashrafi stated.
Transforming the brain by altering its energy source
A stringent version of the ketogenic diet is primarily prescribed to children with epilepsy who do not respond to standard medications. For this diet to be effective, about 90% of a child’s daily caloric intake must derive from fats. When followed rigorously, ketogenic diets can lead to roughly a 50% reduction in seizures for some patients.
This high-fat, carbohydrate-limited diet prompts the liver to produce substances called ketones. These ketones serve as an alternative energy source for neurons when glucose from carbohydrates is scarce. Ashrafi remarked that while the ketogenic diet effectively reduces seizures, many individuals find it challenging to adhere to such a stringent regimen, and even minor deviations can negate its benefits.
While it was commonly accepted that the shift to ketones as an energy source was behind the diet’s anti-seizure effects, the specific biochemical changes in the brain remained elusive. Ashrafi and her team aimed to pinpoint these changes in neurons to potentially identify new targets for effective seizure treatments that require less drastic dietary modifications.
In their experiments, the researchers studied mice exclusively fed high-fat pellets. Under Ashrafi’s guidance, co-senior authors Gabor Egervari, MD, PhD, an assistant professor of genetics and biochemistry, and Vitaly A. Klyachko, PhD, a professor of cell biology and physiology, analyzed genetic activity in the hippocampus—the brain region often involved in seizure activity. They identified hundreds of genetic alterations, many related to synaptic function, the sites where neurons communicate.
After narrowing their focus, the researchers assessed how synaptic behavior changed in the keto diet mice. They discovered that excitatory signals (the neurotransmitters that prompt neighboring neurons to activate) were reduced, whereas inhibitory signals (which diminish neuronal response) were heightened. This shift collectively weakened communication within the brain’s neural circuits, providing an explanation for how the hyperactivity in neurons that triggers epilepsy can be subdued by the ketogenic diet.
Using advanced microscopy, the team also observed that neurons from mice on the ketogenic diet exhibited fewer vesicles containing excitatory neurotransmitters compared to those on a standard diet. These vesicles store the neurotransmitter signals that other cells receive, and this finding was consistent with the identified changes in gene activity.
Ashrafi emphasized that this research illuminates the specific cellular modifications necessary to achieve the anti-seizure effects associated with a ketogenic diet. If these effects could be replicated through medications or alternative interventions, it could lead to innovative approaches to epilepsy treatment.
“Understanding the intersections between diet and disease could reveal promising treatment strategies,” Ashrafi remarked. “If we can mimic the molecular changes that lead to a decrease in vesicle production, we might replicate the diet’s anti-seizure effects without needing a strict dietary overhaul.”
