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

Abstract

Absence epilepsy (AE) is characterized by brief but frequent seizures with loss of consciousness. Existing treatments have heavy side effects, are only partially effective and do not address the comorbidities, including cognitive and social deficits. A tripartite link between seizures, cognitive deficits and diet has been established. We focused on intermittent fasting (IF), a regime where daily periods of fasting alternate with periods of food intake, with no restrictions in the type or quantity of food consumed. To date, the effects of IF on infantile epilepsy have not been addressed. We evaluated the therapeutic potential of a daily, one-month protocol of IF on three established mouse models of AE: the Grm7AAA KI mouse, the Scn2a haploinsufficiency mouse and the pharmacologically-induced AY-9944 mouse model. We show a reduction of the seizure frequency in all models, as well as an improvement of the sociability deficits observed in two of the models, with no adverse effects. Focusing on the Grm7AAA KI model, we performed RNA sequencing in a one of the key brain areas of the absence seizure circuit, the thalamus. We detected a deregulation of genes involved in vascularization associated with the development of malformed blood vessels in epileptic mice. Along with its anti-seizure effects, IF was able to counteract both abnormal gene expression and vessel morphology. This study demonstrates for the first time the positive effects of IF on AE and could facilitate the implementation of the diet in clinical trials.