Misplaced neurons disrupt wiring of the brain

When neurons do not migrate to their proper place during brain development, it causes periventricular heterotopia, a condition associated with seizures and learning difficulties. An international team led by Professor Silvia Cappello, research group leader at LMU’s Biomedical Center and member of the SyNergy Cluster of Excellence, has investigated the characteristics of these misplaced neurons and found an explanation for their hyperactivity.

Using stem cells from patients with periventricular heterotopia, the researchers cultivated a miniature 3D model of the brain, a so-called cerebral organoid, and investigated how the neuronal network functions in the organoid. They found that affected neurons are more excitable and display greater electrical activity. In particular, mutations in a specific gene (DCHS1) lowered the stimulus threshold of these neurons. Moreover, the study revealed that these neurons have a more complex morphology and altered synaptic connections to their neighbors, which could explain why they are overactive. The researchers were able to reverse this hyperactivity by using Lamotrigine, an antiepileptic drug.

“Our findings offer new insights into how the brain's wiring becomes disrupted,” says Cappello. “They could help explain some of the neurological problems associated with the condition and open up new therapeutic approaches for patients in the long term.”

F. Di Matteo et al.: Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia. Nature Communications 2025