Chronicles of brain development

To better understand the role of folate during fetal development, we first need to explore how the human brain forms. Let’s dive into a story of nurture, growth and zippers… 

The central nervous system, comprising the brain and the spinal cord, begins its formation around day 18 post-conception. The early building blocks of the nervous system fold into the shape of a pipe, thus called the neural tube, around the 4th week of development. This tube closes just like a zipper, starting from the middle and extending towards the extremities. From this time forward, a burst of neuronal migration happens through the neural tube, shaping the forebrain, midbrain, and hindbrain. These parts will eventually transition into key regions of the nervous system, involved in cognitive functions such as memory (by the hippocampus and cerebrum), vision (by the retina), sleep and respiration (by the hypothalamus). At this point, the brain also expands massively in size and its surface layer, called the cortex, takes its iconic folded shape, covered with ridges and valleys. In the last trimester, neurons begin to make extensive connections and the cortex matures to allow visual processing, muscle control, and language development.

DNA methylation coordinates the symphony of brain development 

Behind the scenes, the highly dynamic process of brain development is sustained by epigenetic mechanisms. In particular, the addition of a small chemical modification called a methyl group to the DNA can impact the activity of the nearby genes. This process, known as “DNA methylation” plays a major role in health and disease. 

DNA methylation, together with other epigenetic modifications, controls which genes are turned on or off. One can picture DNA methylation as the conductor of an orchestra, shaping the harmonious development of the body. Much like a conductor guiding the musicians through a symphony, DNA methylation directs genes, muting and unmuting them with precise coordination. When crucial genes are improperly methylated, it causes a discordant note in the seamless progression of development. For instance, studies in mouse neurons showed that turning off DNMT3A, a key gene responsible for DNA methylation, results in impaired learning and memory. This shows how fragile the symphony of the brain can be. 

Nurturing brain health with folate supplementation

Where does folic acid fit in the process of brain development? In short, folate is known to support DNA methylation. When we consume folic acid, either from our food or supplements, it is captured by our digestive system and carried to the all cells in our body. Inside the cells, folate donates carbon and methyl groups, which are essential building blocks that help both create new DNA and carry out its methylation. During pregnancy, the folate that the mother consumes is passed to the baby through the placenta. This is process is particularly important because the baby is growing, and therefore its rapidly-dividing cells require sufficient levels of folate, especially in brain cells. Indeed, a number of genes responsible for the creation and survival of neurons are controlled by DNA methylation, and thus are sensitive to the level of folic acid available.

One key process influenced by folate levels is the closure of the neural tube during embryonic development. Failure to fully “zip up” leads to neural tube defects (NTDs), the most severe forms of which can be life-threatening. Many trials have found significant benefits of folic acid supplementation during early pregnancy for preventing NTDs. Indeed, folate deficiency has been observed in mothers of NTD foetuses. Following this observation, folic acid-containing multivitamin supplements were tested and found to prevent NTD recurrence. Other clinical studies have since confirmed the reduction in the risk of NTDs through folic acid supplementation. In addition, evidence from randomized control trials led to mandatory grain fortification with folic acid in around 80 countries worldwide, including USA and Canada.

Folate supplementation in Canada

Recommendation of folic acid supplementation for pregnant women in Canada started in 1993, prompted by findings of the Nutrition Canada Survey conducted across 10 provinces on more than 12,000 Canadians. Results from the survey, and more that came in years after, showed that that 50% of women of childbearing age were at moderate to high risk of folate deficiency. Consequently, in 1998, Canada implemented the fortification of white-wheat flour and pasta with folic acid, in conjunction with recommended supplementation protocols. These measures led to a remarkable 46% decrease in NTD prevalence in the Canadian population by 2007 and to near absence of folic acid deficiency.

In conclusion, folate and its epigenetic contribution are already making a tangible difference in real life, thanks to the extensive research backing its effectiveness. While its precise role in brain development needs more work, the next chapters in this story will likely uncover the intricacies of how folic acid promotes neural tube health at the molecular level.

Learn more:

1. Evaluation report from Canadian health survey  https://www.statcan.gc.ca/en/about/er/chmser  
2. Review on recent insights on periconceptional intake of folic acid among low-risk women in Canada https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290364/ 

We would like to thank Dr. Annie Ciernia from University of British Columbia for her expert review of this article.

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