“The mechanisms have until now been completely unknown.” Fasting diets have long been used in people with epilepsy and have been associated with a reduction in seizures, however, the molecular mechanism behind this approach has always eluded scientists. Until now. Scientists at Boston Children’s Hospital have gained new insights that explain how fasting influences neurons in the brain, which in turn reduces seizures. The finding could open new avenues to treat epilepsy. “This study is the first step in understanding how dietary therapies for epilepsy work,” said first author Dr Christopher J. Yuskaitis, a neurologist with the Epilepsy Center and Epilepsy Genetics Program at Boston Children’s Hospital, in a statement. “The mechanisms have until now been completely unknown.” To address the question of how fasting therapies work, the researchers started with the knowledge that a specific molecular pathway in brain cells, called mTOR, had previously been connected with seizures. Moreover, the overactivation of this pathway is known to lead to increased susceptibility to seizures, and, this very same signaling pathway can also be inhibited by acute fasting. That's because of a signaling molecule called DEPDC5, which can inhibit the activity of the mTOR pathway, and that's where the researchers started their investigation. “When we used an animal model that knocks out DEPDC5 specifically in the brain, we found that we could reduce seizures by using an mTOR inhibitor,” said Yuskaitis. “That gave us the idea to explore the connection between DEPDC5, mTOR, and fasting.” In their mouse seizure model, the researchers of the new study demonstrated that fasting reduces mTOR activity in the brain of the animals. The researchers suggest, based on other findings, that the fasting effect is mainly driven by the lack of three sensing amino acids – leucine, arginine, and glutamine – in the brain when fasting. Going further, the researchers showed that these amino acids are sensed by the signaling molecule DEPDC5. When the researchers used a mice model where DEPDC5 was mutated (meaning the animals could not make the signaling molecule in their brain cells anymore and therefore could not sense the three amino acids any further), the fasting no longer had a beneficial impact on seizure activity in the brains of the animals. “Amino acid sensing seems to be critical for the beneficial effects of fasting on seizures,” Yuskaitis explained. “This suggests that patients with DEPDC5 mutations can’t sense the loss of amino acids and may not benefit from dietary manipulation. But patients who don’t have DEPDC5 mutations may benefit from a targeted dietary strategy.” “We’re hoping this will [help] us uncover additional dietary-based therapies other than ketogenic diet, which is sometimes difficult to follow long term due to side effects,” Yuskaitis added. The researchers now want to follow up these findings with more studies that target specific amino acids in the diets of animals to observe the effects they have on seizures. The study, "DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting," was published in Cell Reports. Source
