SEX-SPECIFIC ROLE OF NEUROPLASTICITY FACTOR BDNF IN BEHAVIORAL, NEUROBIOLOGICAL, AND METABOLIC EFFECTS OF KETOGENIC DIET IN MICE

Ketogenic diet (KD) is a powerful tool for epilepsy and metabolic diseases, while new clinical and animal studies show its potential against mental disorders such as depression, bipolar disorder, and schizophrenia. Several neurobiological pathways have been suggested to mediate effect of KD for the brain and mental health with neuroplasticity factors among them. To explore their role, we estimated the effect of KD in male and female mice deficient in key neuroplasticity factor WT and BDNF heterozygous mice were kept on medium-chain fat-based KD (75% fats, 10% proteins, 3% carbohydrates) or regular chow (RC, 5% fats, 19% protein, 59% carbohydrates) during 4 weeks. Then mice underwent behavioral testing in the open field test, social interaction test, and tail suspension test before they were dissected for ex vivo analysis of brain and blood samples.
BDNF deficiency accelerated body weight gain in both sexes but did not affect behavior. KD reduced body weight gain in males while increased social exploration in females, and both effects were not affected by the genotype. Blood analysis revealed reduced ketogenesis (BHB level) in BDNF^+/- mice. Pro-inflammatory effect of KD was independent of the genotype, while diet-induced decrease of insulin and increase of leptin were found only in WT and BDNF^+/- males respectively. In the brain, BDNF deficiency led to the opposite sex-specific effect in both prefrontal cortex and ventral hippocampus: according to expression of vesicular glutamate and GABA transporters, excitation/inhibition balance was increased in males while decreased in females but was restored by diet in males.