Daily intermittent fasting is an effective multiscale treatment in preclinical models of absence epilepsy

Objective Absence epilepsy is characterized by brief but frequent seizures with loss of consciousness. Existing treatments, which come with heavy side effects, are only partially effective and do not address the associated comorbidities, including cognitive and social deficits. A tripartite link between seizures, cognitive deficits, and diet has been established. Intermittent fasting (IF) is a regime where daily periods of fasting are alternated with periods of food intake. To date, the effects of IF on infantile epilepsy have not been addressed. We evaluated the therapeutic potential of a daily, 1‐month protocol of IF on an established model of generalized absence epilepsy, the Grm7 AAA knock‐in mouse. Methods To assess the effects of IF in mice, we combined electroencephalography, behavior analysis, high‐throughput RNA sequencing, and histology approaches. Results We demonstrate for the first time that daily IF reduces social recognition deficits and epileptic seizures. These effects are associated with the remodeling of the cerebral vascular system. We identified a deregulation of genes involved in vascularization, reflected in the malformation of blood vessels in one of the key brain areas of the absence seizure circuit, the thalamus. Along with its antiseizure effects, we show that IF is able to counteract both abnormal gene expression and vessel morphology. Finally, we demonstrate that IF successfully reduces both seizure frequency and social interaction deficits in the AY‐9944 mouse, a preclinical model of atypical absence seizures, found in more severe epileptic syndromes. Significance Taken together, this study is the first to demonstrate the positive and multiscale effects of IF in the treatment of absence epilepsy.