Ketogenic diet dampens excitatory neurotransmission by shrinking synaptic vesicle pools
Year: 2026
Type: article
Abstract: The ketogenic diet (KD) is a common dietary intervention for treating seizures in intractable childhood epilepsies and has been proposed to improve disease outcome in neurodegenerative disorders. Despite its clinical applications, we know little about how this diet impacts brain circuitry and neuronal function to elicit its protective effects. Here, we examined the impact of the KD on hippocampal function through integrative analysis of gene expression, epigenetics and neurotransmission. We found that KD induces profound transcriptional reprogramming of the hippocampus, including dampened expression of numerous synaptic genes. Through proteomic analysis of histone variants and post-translational modifications, we uncovered significant changes in activating and repressive histone marks in the hippocampus of KD mice. To determine how transcriptional rewiring of the hippocampus under KD impacts neurotransmission, we performed electrophysiological recordings of neurotransmission and synaptic dynamics at excitatory CA3-CA1 synapses. We found that KD diminishes synaptic gain and dampens short-term plasticity at excitatory synapses, resulting in reduced integration of synaptic inputs at the circuit level. Combining electrophysiology and electron microscopy, we determined that effects of KD in excitatory synapses are caused by a reduction in size of the readily releasable pool of synaptic vesicles, as well as the total vesicle pool. Our findings show that the ketogenic diet triggers synaptic remodeling in the hippocampus, driven by broad transcriptional and epigenetic changes that reduce synaptic vesicle pools and short-term plasticity at excitatory synapses ultimately dampening excitatory synaptic gain and integration at the circuit level. These synaptic adaptations may represent a major mechanism underlying the anti-epileptic effects of this diet.
Source: Cell Reports
Language: English
Topic: Diet and metabolism studies
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Genome Technology Access Center, Nutrition Obesity Research Center, University of Washington, Brain and Behavior Research Foundation, Whitehall Foundation, Foundation for Barnes-Jewish Hospital, National Alliance for Research on Schizophrenia and Depression, Chan Zuckerberg Initiative, St. Louis Children's Hospital, National Institutes of Health, McDonnell Center for Systems Neuroscience, Center for Cellular Imaging, Washington University, National Institute on Alcohol Abuse and Alcoholism, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G2337220457, G2806300442, G3610738371, G4673675110, G5157015781, G541477730, G627181035, G6288698579, G6325523995, G6570768585, G766674393, G8505683480, G9000081704, Epigenetic-metabolic aspects of alcohol use disorder and early developmental alcohol exposure, Quantitative mass spectrometry for comprehending epigenetic mechanisms in a new underlying neurological developmental disorder
OpenAlex ID: W7128477213