How Stem Cell Models Are Uncovering the Impact of Epilepsy Genes on Brain Regions

Recent research utilizing human stem cell-derived models has shed light on how genetic mutations associated with epilepsy affect different areas of the brain. In particular, a study from UCLA, published in Cell Reports, investigates developmental and epileptic encephalopathy type 13 (DEE-13), caused by variants in the SCN8A gene. This gene encodes Nav1.6, a vital sodium channel responsible for electrical signaling in neurons. Children with DEE-13 often face severe seizures along with developmental delays, intellectual disabilities, and autism spectrum disorder.

Using advanced 3D brain models called 'assembloids'—which combine diverse neuronal cell types—researchers focused on two key brain regions: the cortex, involved in movement and thinking, and the hippocampus, essential for learning and memory. The models revealed that SCN8A variants induce hyperactivity in cortical neurons, simulating seizure activity. Conversely, in the hippocampus, these variants disrupt normal brain rhythms vital for learning, primarily by reducing specific inhibitory neurons that serve to regulate neural activity.

These findings help explain why patients with epilepsy often experience problems beyond seizures themselves, such as behavioral and cognitive issues. Dr. Ranmal Samarasinghe from UCLA emphasized that these cognitive challenges are not mere side effects but stem from distinct disruptions within the hippocampus, highlighting the importance of targeting these specific brain regions for potential treatments.

To validate their models, the team compared neural activity in stem cell assembloids with recordings from the hippocampi of epilepsy patients. Results showed similar abnormal brain rhythms in both. Regions unaffected by seizures in patients displayed normal activity in corresponding models, confirming the relevance of stem cell-based research.

This breakthrough is the first to recreate and analyze neural activity patterns of human hippocampal tissue in vitro, opening new avenues for understanding and treating conditions like epilepsy, autism, and Alzheimer’s disease—all of which involve hippocampal dysfunction.

According to co-senior researcher Bennett Novitch, these models offer a powerful tool to study how various brain diseases impact learning and memory circuits, potentially leading to new therapies. However, the scientists warn that progress is hindered by inconsistent federal funding, which delays experiments and technological advancements. Dr. Samarasinghe stressed that such delays not only stall scientific discovery but also prolong suffering for children and families affected by these disorders.

In summary, stem cell-derived brain models have demonstrated their potential to replicate human neural patterns and disease processes, providing valuable insights into epilepsy and related conditions. Continued support for this research is essential to develop targeted and effective treatments that address both seizures and cognitive impairments.