Deficient or Excess Folic Acid Supply during Pregnancy Alter Cortical Neurodevelopment in Mouse Offspring

Angelo Harlan De Crescenzo, Alexios A. Panoutsopoulos, Lyvin Tat, Zachary Schaaf, Shailaja Racherla, Lyle Henderson, Kit Yi Leung, Nicholas D.E. Greene, Ralph Green, Konstantinos S. Zarbalis

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Folate is an essential micronutrient required for both cellular proliferation through de novo nucleotide synthesis and epigenetic regulation of gene expression through methylation. This dual requirement places a particular demand on folate availability during pregnancy when both rapid cell generation and programmed differentiation of maternal, extraembryonic, and embryonic/fetal tissues are required. Accordingly, prenatal neurodevelopment is particularly susceptible to folate deficiency, which can predispose to neural tube defects, or when effective transport into the brain is impaired, cerebral folate deficiency. Consequently, adequate folate consumption, in the form of folic acid (FA) fortification and supplement use, is widely recommended and has led to a substantial increase in the amount of FA intake during pregnancy in some populations. Here, we show that either maternal folate deficiency or FA excess in mice results in disruptions in folate metabolism of the offspring, suggesting diversion of the folate cycle from methylation to DNA synthesis. Paradoxically, either intervention causes comparable neurodevelopmental changes by delaying prenatal cerebral cortical neurogenesis in favor of late-born neurons. These cytoarchitectural and biochemical alterations are accompanied by behavioral abnormalities in FA test groups compared with controls. Our findings point to overlooked potential neurodevelopmental risks associated with excessively high levels of prenatal FA intake.

Original languageEnglish (US)
Pages (from-to)635-649
Number of pages15
JournalCerebral Cortex
Issue number1
StatePublished - Jan 1 2021


  • cortical development
  • folate metabolism
  • mouse
  • neurogenesis
  • projection neurons

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience


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