Lab-grown brain models reveal how epilepsy drug alters fetal development

It is known that the antiepileptic drug valproate increases the risk of developmental disorders in unborn children. A study conducted by the Karlsruhe Institute of Technology (KIT), the Heidelberg Academy of Sciences and Humanities, the University of Tübingen, and the University Heidelberg using lab-grown tissue models of the human brain gives new insights into the effects this drug has on early brain development. They open up new avenues for research to mitigate the risk during pregnancy. The study has been published in the Molecular Psychiatry journal. (DOI: 10.1038/s41380-026-03585-5) 

With about 40 million patients, epilepsy counts among the most common neurological diseases worldwide. As a standard antiepileptic drug, valproate also plays a role in the treatment of bipolar disorders. Since it is known that valproate increases the risk of neurodevelopmental disorders, such as autism spectrum disorders, special warnings apply to women of childbearing age who take the drug. It has not been fully understood so far, however, how valproate actually affects the mechanisms of early brain development. "We used lab-grown models of the human brain to investigate for the first time how the drug alters the extracellular matrix and how those alterations in turn affect processes within individual cells," said Zeynep Yentür, research assistant in Professor Simone Mayer's working group at KIT's Zoological Institute (ZOO).

The model system: Human brain organoids

For their study, the researchers used cerebral organoids, i.e. three-dimensional tissue structures grown from human stem cells, which served as models representing different development stages of the prenatal brain. They exposed these organoids to valproate for 30 days to simulate continuous exposure during the early development stages. Then, the researchers investigated the impact of the medication on the tissue, cellular, and molecular levels.

The results show that the drug significantly reduces cell proliferation, disrupts the ordered structure of critical development regions, and impairs the development of progenitor cells into mature neurons. The impact on the extracellular matrix is particularly strong, causing structural changes, increased stiffness, and impairment of intercellular communication and signaling processes, which are essential for normal brain development. Despite the known risks, valproate is the only effective treatment option for certain female epilepsy patients. "With our research, we want to contribute to a better understanding of how the medication actually works to identify new avenues of research for mitigating the risk to fetuses," said Yentür. It is obvious that the findings from a lab study using tissue models cannot replace clinical data, but they do provide important insights into basic development mechanisms.

Research as part of the "3D Matter Made to Order" cluster of excellence

The study was launched as a collaboration of KIT, the Heidelberg Academies of Sciences and Humanities, the University of Tübingen, and the University Heidelberg as part of the 3D Matter Made to Order (3DMM2O) Cluster of Excellence. The 3DMM2O Cluster of Excellence is a joint initiative of KIT and the UniversityHeidelberg. It aims at bringing 3D Additive Manufacturing from the macroscale to the micro, nano, and eventually to the molecular scale. The goal is to use nano printing for manufacturing single components and entire systems at maximum process speeds and resolutions for novel applications in materials and life sciences.