Brain Organoid Study Reveals How Valproate Affects Early Brain Development

Key finding: Researchers have identified alterations in the extracellular matrix as a central mechanism by which the antiepileptic drug valproate impacts fetal brain development.

Background and Context

Valproate is a standard antiepileptic drug also used for bipolar disorders. It is known to be associated with an increased risk of neurodevelopmental disorders, such as autism spectrum disorders, in unborn children.

According to the study authors, the mechanisms by which valproate affects early brain development were not fully understood prior to this research.

The study was conducted as part of the 3D Matter Made to Order (3DMM2O) Cluster of Excellence, a joint initiative of KIT and Heidelberg University.

Methodology

Researchers used cerebral organoids—three-dimensional tissue structures grown from human stem cells that represent prenatal brain development stages.

To simulate continuous exposure during early development, the organoids were exposed to valproate for a period of 30 days. The effects were then analyzed at the tissue, cellular, and molecular levels.

Key Findings

The study reported several effects of valproate exposure on the organoids:

• Reduced cell proliferation
• Disruption of the ordered structure of critical development regions
• Impaired development of progenitor cells into mature neurons
• Significant changes to the extracellular matrix, including:
  • Structural changes
  • Increased stiffness
  • Impairment of intercellular communication and signaling processes

The research identified these alterations in the extracellular matrix as a key mechanism of the drug's action.

Statements from Researchers

Zeynep Yentür, a research assistant in Professor Simone Mayer's working group at KIT's Zoological Institute, stated:

"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."

Yentür added:

"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."

Study published in: Molecular Psychiatry (DOI: 10.1038/s41380-026-03585-5)

Collaborating institutions: Karlsruhe Institute of Technology (KIT), Heidelberg Academy of Sciences and Humanities, University of Tübingen, and Heidelberg University