Ketogenic Diet Modulates the Proteome of the GAERS Model of Genetic Absence Epilepsy

This study investigates the effects of a ketogenic diet (KD) on the brain proteome in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model of genetic absence epilepsy. The ketogenic diet is a therapeutic intervention for epilepsy, yet its mechanisms remain incompletely understood. Thirty-day-old male GAERS rats were fed a KD (88.8% fat, 10.2% protein, 1% carbohydrate; n = 4) or a normal diet (ND; n = 3), with Wistar rats (n = 3) as healthy controls. A shotgun proteomics approach with data-dependent acquisition was used to analyze the somatosensory cortex (SCx) and hippocampus (Hipp). Data were processed with MaxQuant and Perseus. Compared to Wistars, GAERS-ND rats showed significant alterations in 526 proteins in SCx and 612 in Hipp. KD treatment significantly altered 122 proteins in SCx and 124 in Hipp of GAERS. Notably, KD reversed the expression of 22 proteins in SCx and 32 in Hipp to levels observed in controls. Most KD-affected proteins were synaptic (72% SCx, 76.6% Hipp) and mitochondrial. Pathway analysis indicated KD regulates axon guidance, neurodevelopment, and metabolism in SCx, and autophagy, mitophagy, and Rho GTPase signaling in Hipp. The workflow of the experimental design is provided in Fig. 1.