Key takeaways
- UCLA researchers used patient-derived stem cells to model how gene variants that cause developmental and epileptic encephalopathy type 13, a rare genetic childhood epilepsy, affect different regions of the brain.
- The team discovered that the same variants drive seizure-like hyperactivity in the cortex but disrupt memory-related neural rhythms in the hippocampus by depleting inhibitory neurons — offering insight into why seizure medications alone may not address the full scope of symptoms.
- By reproducing abnormal brain activity observed in patients, the study establishes the first hippocampal assembloid model, creating a new platform for studying epilepsy, autism, Alzheimer's disease and other brain disorders.
For families of children with severe epilepsy, controlling seizures is often just the beginning of their challenges. Even in cases where powerful medications can reduce seizures, many children continue to face difficulties with learning, behavior and sleep that can be just as disruptive to daily life.
New stem cell-based research from UCLA, just published in Cell Reports, provides an early step toward understanding why current treatments often fall short, pointing to the distinct effects that single disease-causing gene variants can have across different regions of the brain.
The study focuses on developmental and epileptic encephalopathy type 13, or DEE-13, a rare childhood condition caused by certain variants in the SCN8A gene. SCN8A encodes Nav1.6, a sodium channel critical for generating and transmitting electrical signals in neurons. Children with DEE-13 experience frequent seizures as well as developmental delays, intellectual disability, and autism spectrum disorder.
Different brain regions, different problems
Using patient-derived induced pluripotent stem cells, the researchers generated advanced models known as 3D assembloids of two key brain areas: the cortex, which is essential for movement and higher-order thinking, and the hippocampus, which supports learning and memory. The results revealed strikingly different effects depending on the brain region.
In cortical models, the SCN8A variants made neurons hyperactive, mimicking seizure activity. In hippocampal models, however, the variants disrupted the brain rhythms associated with learning and memory. This disruption stemmed from a selective loss of specific hippocampal inhibitory neurons — the brain's traffic cops that regulate neural activity.
These findings may help explain why patients with epilepsy often struggle with symptoms beyond seizures.
"Seizures are what bring families to the clinic, but for many parents, the bigger daily struggles are the other symptoms — problems with learning, behavior and sleep," said Dr. Ranmal Samarasinghe, co-senior author and clinical neurologist at UCLA. "What we found is that these cognitive problems aren't just side effects of seizures. They likely arise from distinct disruptions in the hippocampus itself."
Understanding these hippocampal disruptions is the first step toward identifying treatments that can help with the full range of symptoms, Samarasinghe added.
Video: Live recordings show neural activity in hippocampal assembloids derived from patient stem cells. In the healthy control (left), neurons fire independently. In the assembloid with the SCN8A gene variant (right), neurons fire together in sudden flashes — an abnormal pattern associated with seizures. (Courtesy of Colin Mccrimmon, Samarasinghe Lab)
Validating the model against human disease
To confirm their findings, the researchers compared brain recordings from people with epilepsy to stem cell-derived hippocampal assembloids. They looked at seizure-prone regions of the patients' hippocampi as well as regions unaffected by seizures. Abnormal brain rhythms appeared in both the patients' seizure "hot spots" and in assembloids carrying SCN8A variants. In contrast, seizure-free brain regions and assembloids without the variants showed normal activity.
"That was an important moment," said Samarasinghe, who is also an assistant professor of neurology and member of both the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and the Intellectual and Developmental Disability Research Center at UCLA. "It showed us that the disease processes we see in stem cell models mirror what happens in patients."
Beyond its implications for epilepsy treatment, the study breaks new ground as the first to successfully create and characterize neural activity patterns in human hippocampal assembloids.
By demonstrating that stem cell-derived hippocampal tissue can generate authentic brain rhythms, the research provides a powerful new platform for investigating other conditions that affect learning and memory.
The technique could prove valuable for studying autism, schizophrenia and Alzheimer's disease — all conditions where hippocampal function plays a crucial role.
"This is a foothold into a whole new area of research," said Bennett Novitch, co-senior author, professor of neurobiology and member of both the UCLA Broad Stem Cell Research Center and the Intellectual and Developmental Disability Research Center. "We now have a system to ask how different diseases affect learning and memory circuits, and in the future to explore whether experimental therapies might improve brain activity in these models."
The importance of sustained NIH funding
While the study highlights a major advance in modeling human brain circuits, the researchers cautioned that continued progress depends on stable federal research support.
"In my case, 100% of my NIH funding was suspended," Samarasinghe said. "Without that support, we've had to halt experiments that took months to set up and put everything in the freezer, waiting to see if funding will return. Those kinds of disruptions make it incredibly difficult to move discoveries forward."
Novitch added that the stop-and-start funding climate has left labs caught between tremendous new capabilities and the inability to fully use them. "We're able to create human brain-like specimens that finally allow us to probe the underlying causes of disease," he said. "This is a goldmine for understanding epilepsy, autism, Alzheimer's and other conditions — but we're being impeded from taking advantage of what's now technically possible."
Both scientists stressed that the stakes go beyond academic progress. "Families come to us desperate for better options," Samarasinghe said. "Without NIH funding, we can't push forward the kinds of discoveries that could one day ease the daily struggles of children with epilepsy and related disorders. These delays don't just set back science — they prolong suffering."
This research was funded by the National Institutes of Health, CURE Epilepsy, the International SCN8A Alliance, the Simons Foundation, the UCLA Intellectual and Developmental Disabilities Research Center, a UCLA Broad Stem Cell Research Center Innovation Award, the In Memory of Christina Louise George Fund and the Michael R. Bloomberg Revocable Trust.
