Ketogenic Diet-Associated Remodeling of the Cortical Proteome in Rats With Genetic Absence Epilepsy

Abstract

Purpose This study investigated the effects of ketogenic diet (KD) intervention on the cortical proteome in genetic absence epilepsy rats from Strasbourg (GAERS), a well-established model of absence epilepsy. The ketogenic diet is a therapeutic intervention for epilepsy, yet its mechanisms remain incompletely understood.Method 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 (DDA) was used to analyze the somatosensory cortex (SCx), a key cortical driver of absence seizures. Data were processed with MaxQuant and Perseus.Findings Compared to Wistars, GAERS-ND rats showed significant alterations in 526 proteins in SCx and KD treatment significantly altered 121 proteins in SCx of GAERS. Notably, KD was associated with partial shifts in the expression patterns of 22 proteins toward those observed in Wistar controls. Most KD-affected proteins were synaptic (72% SCx) and mitochondrial. Pathway analysis indicated that ketogenic diet-associated protein changes were enriched in axon guidance, neurodevelopment, and metabolic pathways in the somatosensory cortex.Conclusion Together, these results suggest that synaptic and mitochondrial protein alterations in this region are associated with cortical molecular adaptations observed under ketogenic diet administration in absence epilepsy.