Addressing a folate imbalance in fetal cerebrospinal fluid can decrease the incidence of congenital hydrocephalus

Area of Science:

• Neuroscience
• Developmental Biology
• Biochemistry

Background:

• Fetal-onset hydrocephalus (HC) affects 1:500-1:5000 births, causing severe neurological deficits due to abnormal cerebrospinal fluid (CSF) dynamics and cerebral cortex development.
• Previous research indicated that CSF from affected fetuses in the hydrocephalic Texas rat model induces neural progenitor cell cycle arrest.

Purpose of the Study:

• To investigate the role of folate metabolism alterations in the CSF of developing cerebrums as a cause of HC.
• To determine if specific folate supplementation could ameliorate HC and improve brain development in the hydrocephalic Texas rat model.

Main Methods:

• Identified three folate enzymes in the CSF of developing rat cerebrums.
• Assessed the association between 10-formyltetrahydrofolate dehydrogenase levels and HC incidence.
• Administered daily supplementation of tetrahydrofolic acid and 5-formyltetrahydrofolic acid or folic acid to pregnant dams.

Main Results:

• Low levels of 10-formyltetrahydrofolate dehydrogenase were associated with HC in the hydrocephalic Texas rat.
• Supplementation with tetrahydrofolic and 5-formyltetrahydrofolic acids significantly reduced HC incidence and improved brain development.
• Folic acid supplementation paradoxically increased the incidence of congenital HC in this model.

Conclusions:

• Alterations in folate metabolism, specifically low 10-formyltetrahydrofolate dehydrogenase, contribute to fetal HC in the hydrocephalic Texas rat.
• Targeted maternal folate supplementation with specific metabolites offers a potential therapeutic strategy for congenital HC.
• The complexity of folate metabolism in brain development necessitates careful consideration of folate species used in supplementation.