Prenatal exposure to a maternal LP diet decreases BDNF expression in the brains of the neonatal offspring

Abstract

Prenatal exposure to a maternal low protein diet has been known to cause cognitive deficits in the adult progeny. Maternal low protein diets induce visual and spatial memory impairment, deficits in learning and memory, as well as a host of behavioral abnormalities in the adult progeny. However, the underlying causes and the molecular mechanisms have not been identified. Herein, we demonstrate that a maternal low protein (LP) diet causes, in the brains of the male and female neonatal rat offspring, an attenuation in the basal expression of the Brain‐derived neurotrophic factor (BDNF), a neurotrophin essential for neuronal survival and indispensable for learning and memory. Sprague‐Dawley female rats were fed either a 20% normal protein diet (NP) or an 8% low protein (LP) diet inducted at three weeks before breeding and continued for the entirety of the gestation period. Maternal LP diet caused a significant reduction in the Bdnf expression in the whole brains of the male and female neonatal rat offspring. We delineated the molecular mechanisms further, and found that a maternal LP diet –1) decreases cAMP levels and the ensuing protein kinase A (PKA) activation, that 2) consequently reduces CREB activation, which 3) culminates in a significant reduction in cAMP response element binding protein (CREB) binding to the Bdnf promoters – in the brains of male and female neonatal offspring. We further show that prenatal exposure of the neonatal male and female offspring to a maternal LP diet results in a characteristic inactive or repressed exon I and exon IV promoter of the Bdnf gene in the brain, as evidenced by fluxes in signatory hallmarks in the enrichment of acetylated and trimethylated histones in the nucleosomes that envelop the exon I and exon IV promoters of the Bdnf gene. Our study shows that prenatal exposure to a maternal LP diet results in the attenuation of basal Bdnf gene expression in the brains of the neonatal progeny through reduced activation of the cAMP/PKA/CREB pathway accompanied by changes in histone modification that make the exon I and exon IV promoter of the Bdnf gene refractory to transactivation.Support or Funding InformationThis work was supported by National Institutes of Health, Grant # R01AG0145264, to Dr. Othman Ghribi.