For families of children with severe epilepsy, managing seizures is often just the start of a long journey. Even when potent medications can reduce seizures, many children continue to grapple with learning difficulties, behavioral issues, and sleep disruptions that significantly impact daily life. New research from UCLA, published in Cell Reports, marks an early step in understanding why current treatments often fall short, highlighting the distinct effects that single gene variants can have across different brain regions.
The study zeroes in on developmental and epileptic encephalopathy type 13 (DEE-13), a rare childhood condition linked to variants in the SCN8A gene. This gene encodes Nav1.6, a sodium channel crucial for generating and transmitting electrical signals in neurons. Children with DEE-13 frequently experience seizures, developmental delays, intellectual disabilities, and autism spectrum disorder.
Distinct Brain Regions, Distinct Challenges
Utilizing patient-derived induced pluripotent stem cells, UCLA researchers developed advanced models known as 3D assembloids of two critical brain areas: the cortex, essential for movement and higher-order thinking, and the hippocampus, which supports learning and memory. The results revealed profoundly different effects depending on the brain region.
In cortical models, SCN8A variants caused neurons to become hyperactive, simulating seizure activity. Conversely, in hippocampal models, the variants disrupted brain rhythms associated with learning and memory due to a selective loss of specific inhibitory neurons — the brain’s “traffic cops” that regulate neural activity.
These findings may illuminate why epilepsy patients 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.”
Validating the Model Against Human Disease
To confirm their findings, the researchers compared brain recordings from individuals with epilepsy to stem cell-derived hippocampal assembloids. They examined seizure-prone regions of the patients’ hippocampi and regions unaffected by seizures. Abnormal brain rhythms were present in both the patients’ seizure “hot spots” and in assembloids carrying SCN8A variants. In contrast, seizure-free brain regions and assembloids without the variants exhibited 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.
A Platform for Broader Research
By demonstrating that stem cell-derived hippocampal tissue can generate authentic brain rhythms, the research provides a powerful new platform for investigating other conditions affecting 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 utilize 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.
