Vitamin A deficiency impairs postnatal cognitive function via inhibition of neuronal calcium excitability in hippocampus

Abstract

Vitamin A (VA) is important for postnatal brain development, and VA deficiency (VAD) can cause learning and spatial memory deficits in rats. Most of the biological functions of VA are mediated by retinoic acid (RA). To investigate the mechanisms underlying VA deficits, mother rats were fed elemental diets to achieve blood VA levels classified as normal, deficient or severely deficient. Shuttle box and Morris water maze tests revealed impairments in learning ability and spatial memory, respectively, in adolescent VAD rats (p 30-35). Electrophysiology showed weaker long-term potentiation in VAD rats compared to VA normal rats. Examination of NMDA-induced calcium (Ca(2+) ) excitability revealed decreased excitability in hippocampal slices from VAD rats during postnatal development. Relative to VA normal rats, VAD rats also had decreased NMDA receptor NR1 mRNA and protein expression in later stages of postnatal development (p 10-30), as well as differences in retinoic acid receptor (RARα) mRNA and protein expression. Furthermore, primary hippocampal neurons in culture showed increased neuronal Ca(2+) excitability in response to all-trans-RA or 9-cis-RA, coupled with increases in RARα and NR1 expression similar to those observed in vivo. We also found weaker calcium excitability and lower expression of NR1 mRNA and protein after specific silencing of RARα. Finally, we found that RA signals affected the expression of NR1 do not directly through transcriptional regulation. These data support the new idea that continuous postnatal VAD inhibits RARα expression, which decreases NR1 expression via no direct transcriptional regulation and then inhibits hippocampal neuronal Ca(2+) excitability which affects long-term potentiation, finally producing deficits in active learning and spatial memory in adolescence.