Brain research in the Petri dish: Organoids can be used to understand disease processes.
Photo Credit: Amadeus Bramsiepe, KIT
Scientific Frontline: Extended "At a Glance" Summary: Valproate and Early Brain Development
The Core Concept: A recent study utilizes 3D human brain organoids to investigate how the widely used antiepileptic drug valproate disrupts early fetal brain development and contributes to neurodevelopmental disorders.
Key Distinction/Mechanism: Researchers discovered that valproate alters the extracellular microenvironment, making it stiffer. This physical and structural change inhibits cell proliferation, disrupts key developmental zones, and impairs the crucial signaling required for progenitor cells to properly mature into functional nerve cells.
Major Frameworks/Components:
- Human Brain Organoids: 3D tissue structures grown in the laboratory from stem cells, used to simulate and observe human prenatal brain development over a 30-day drug exposure period.
- Extracellular Environment Analysis: Investigating how the structural and mechanical stiffening of the space surrounding cells impairs central neural communication.
- Multiomics Profiling: Evaluating the valproate-induced alterations simultaneously across tissue, cellular, and molecular levels.
Branch of Science: Neuroscience, Neuropharmacology, and Developmental Biology.
Future Application: These foundational laboratory insights pave the way for developing targeted therapeutic approaches and risk-minimization strategies for pregnant patients who rely on valproate for seizure control.
Why It Matters: Epilepsy affects roughly 40 million people globally, and while valproate is an essential treatment for many, its known link to neurodevelopmental disorders (such as autism spectrum disorders) in fetuses makes understanding its exact cellular disruption mechanisms a critical step toward protecting unborn children.
The increased risk of brain developmental disorders in unborn children due to the antiepileptic drug valproate is well known. A study by the Karlsruhe Institute of Technology (KIT), the Heidelberg Academy of Sciences, the University of Tübingen and the University of Heidelberg using laboratory-grown tissue models of the human brain now provides new insights into how the drug influences early brain development – and thus opens up new approaches for research into risk minimization during pregnancy.
Epilepsy is one of the most common neurological diseases worldwide, affecting around 40 million people. Valproate is a common drug used to treat epilepsy and is also used for bipolar disorder. Because of the known increased risk of neurodevelopmental disorders such as autism spectrum disorders, special warnings apply when taking valproate for women of childbearing age. However, how exactly the drug affects the mechanisms of early brain development has so far been insufficiently researched. „We used laboratory-grown tissue models of the human brain to investigate for the first time how the drug affects the cellular environment and how these changes, in turn, influence processes inside individual cells“, explains Zeynep Yentür, research associate in Professor Simone Mayer's research group at KIT's Zoological Institute (ZOO).
Human brain organoids as a model system
The researchers used cerebral organoids for their study. These are three-dimensional tissue structures grown from human stem cells that replicate different developmental stages of the prenatal brain. These organoids treated her with valproate for over 30 days to simulate sustained exposure during early stages of development. The researchers then examined the effects of the tissue, cell, and molecular levels.
The results show that the drug significantly inhibits cell proliferation, disrupts the ordered structure of important developmental zones, and causes precursor cells to develop less well into mature nerve cells. The extracellular environment of cells is particularly affected: it changes structurally, becomes stiffer, and impairs central communication and signaling processes that are essential for normal brain development. For some patients with epilepsy, valproate is the only effective treatment option despite the known risks. „With our research, we aim to contribute to a better understanding of the drug's mechanisms of action in order to enable new long-term research approaches to minimize risk in fetuses”, says Yentür. As a laboratory study of tissue models, the results do not replace clinical data, but they provide important clues to fundamental developmental mechanisms.
Research in the Cluster of Excellence 3D Matter Made to Order
The study was conducted in collaboration between KIT, the Heidelberg Academy of Sciences, the University of Tübingen and the University of Heidelberg within the Cluster of Excellence 3D Matter Made to Order (3DMM2O). The 3DMM2O Cluster of Excellence, jointly supported by KIT and Heidelberg University, explores three-dimensional additive manufacturing techniques – from the molecular level to macroscopic dimensions. Components and systems are to be created using the nanoprinting process with the highest process speed and resolution and create the conditions for novel applications in materials and life sciences.
Reference material: What Is: Organoid
Published in journal: Molecular Psychiatry
Authors: Zeynep Yentür, Lizia Branco, Kseniia Sarieva, Daria Andreeva, Theresa Kagermeier, Christina Kulka, Mohamed A. Jarboui, Federico Colombo, Florencia Diaz, Pierre Collignon, Katharina Becker, Christine Selhuber-Unkel, and Simone Mayer
Source/Credit: Karlsruhe Institute of Technology
Reference Number: ns043026_01
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