Summary: New research in mice indicates that excess folic acid — the synthetic form of folate used in food fortification and supplements — can affect brain development. Imbalances between folic acid and vitamin B12 altered neuronal growth and synaptic connectivity in the developing cerebral cortex, prompting questions about current fortification practices and optimal prenatal nutrient balance.
While folic acid fortification has clearly reduced neural tube defects, these new findings raise concerns about potential unintended effects on neurodevelopment. The authors call for further research to define safe and effective folate intake during pregnancy, and to clarify how folic acid, natural folates, and vitamin B12 interact to influence brain health.
Key Facts:
- Folic acid added to foods and prenatal vitamins has reduced neural tube defects, but excess intake may have other effects on fetal brain development.
- In mice, high folic acid or low vitamin B12 disrupted cortical neuron development and reduced neuronal interconnections.
- Folinic acid, a biologically active natural form of folate, produced minimal effects in the same experimental conditions, indicating different forms of folate act differently in the body.
Source: UC Davis
Background: Folate (vitamin B9) is essential for preventing neural tube defects such as spina bifida. Because the neural tube closes early in pregnancy — about 28 days after conception — many countries fortify staple foods and supplements with folic acid, the synthetic and stable form of folate, to ensure adequate intake before pregnancy is recognized. This public-health measure has substantially reduced neural tube defects worldwide.
Despite the clear benefits against neural tube defects, researchers caution that overconsumption of folic acid — particularly when combined with low vitamin B12 status — could affect brain development in other ways. The study authors note that food manufacturers often add folic acid to cereals and other products, and some people may exceed the recommended upper daily limit of 1,000 micrograms of folate.
The consequences of high folic acid and low B12
In a study published in Communications Biology, investigators from the UC Davis School of Medicine and the UC Davis MIND Institute examined how prenatal diets varying in folic acid and vitamin B12 affected mouse brain development. Earlier work from this group showed that both excessive and deficient maternal folate can alter prenatal neurogenesis and long-term neuronal structure.
For the current experiments, researchers provided pregnant mice with controlled diets: a baseline diet with normal folic acid and B12, and four experimental diets characterized by either high folic acid, low B12, high folic acid plus low B12, or high folinic acid (a natural, reduced form of folate). The team then used multiple imaging approaches to assess how these diets influenced development of the cerebral cortex, a brain region central to cognition, emotion, and many psychiatric conditions that begin in childhood.
The investigators found that excess folic acid or vitamin B12 deficiency altered the timing and pattern of neuronal development. Neurons that typically arise later in cortical development were produced over an extended period and took longer to migrate and settle into their proper positions. Both high folic acid and B12 deficiency were also associated with fewer neuronal interconnections — a reduction in dendritic complexity and synaptic density — though the most pronounced effects occurred when high folic acid and low B12 were combined.
Importantly, when folic acid was substituted with folinic acid at similar high levels, the researchers observed virtually no adverse effects on the developing mouse brains. This difference highlights that not all forms of folate behave the same way in the body and suggests that the choice of folate compound may influence developmental outcomes.
The authors emphasize that these are animal-model findings and do not establish direct effects in humans. Mice and humans differ in metabolism, including how folic acid is processed. The team is extending their work using human brain organoids — three-dimensional cell models that include multiple neural cell types — to better understand how folate forms and B12 status impact human neural development.
“There is complexity in how folic acid, folinic acid and vitamin B12 interact,” said co-senior author Konstantinos Zarbalis. “We are still defining how much folate and which form is optimal to prevent neural tube defects while avoiding potential risks to brain development.”
Co-authors on the study include Lyvin Tat, Noemi Cannizzaro, Zachary Schaaf and Shailaja Racherla of UC Davis, and Teodoro Bottiglieri of Baylor Scott & White Research Institute. Funding was provided in part by the National Institute for Child Health and Human Development (R01HD107489), the National Institute of Mental Health (R21MH115347), Shriners Hospitals for Children, and the MIND Institute’s Intellectual and Developmental Disabilities Research Center (P50HD103526).
About this neurodevelopment research news
Author: Lisa Howard
Source: UC Davis
Contact: Lisa Howard – UC Davis
Image: Image credit: Neuroscience News
Original Research: Open access. “Prenatal folic acid and vitamin B12 imbalance alter neuronal morphology and synaptic density in the mouse neocortex” by Ralph Green et al., Communications Biology (study examines how prenatal folic acid excess and B12 deficiency affect neuronal arborization and synaptic density in the mouse neocortex).
Abstract
Prenatal folic acid and vitamin B12 imbalance alter neuronal morphology and synaptic density in the mouse neocortex
Previous studies indicate that both insufficient and excessive maternal folic acid (FA) intake can alter offspring neurodevelopment by affecting prenatal neurogenesis. Prior work from this group showed that either deficient or excessive FA supply reduced dendritic arborization of cortical projection neurons. The current findings report that excessive FA decreases arborization of deep-layer projection neurons but not upper-layer neurons; this reduced complexity was not observed when FA was replaced by folinic acid. Vitamin B12 deficiency produced even larger decreases in neuronal arborization across layers, particularly when combined with FA excess. Both FA excess and B12 deficiency also affected synaptic density and morphology, suggesting that an imbalance in these interacting micronutrients may pose risks to neurodevelopment.