Folate Receptor Alpha (FRα) and the Developing Brain: From Molecular Function to Neurodevelopmental Outcomes

Folate receptor alpha (FRα) is a high-affinity transporter responsible for delivering folate (vitamin B9) into the central nervous system (CNS), supporting the synthesis of nucleic acids, amino acids, lipids, and signaling molecules through one-carbon transfer pathways. Beyond its transport function, upon activation by folate, FRα modulates extracellular signaling, regulates membrane and cytosolic proteins, and gene transcription. Disruption of FRα, whether functional or structural, can impair CNS folate availability and lead to developmental abnormalities or neurological dysfunction, with the clinical consequences depending on the timing, severity, and presumably on the individual genetic background. Together, these insights position FRα as both a multifunctional regulator of cellular fate and a key molecular interface connecting folate metabolism, brain development, and neurobehavioral outcomes. This narrative review synthesizes the current state of knowledge on FRα, highlighting its roles in neuronal and glial differentiation, CNS maturation, and neural plasticity, while also examining the links between impaired FRα function and a spectrum of developmental and neuropsychiatric conditions. It also outlines the need for broader population-based studies to evaluate the diagnostic value of FRα autoantibodies and the therapeutic potential of folate supplementation.