Key TakeawaysUCLA 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.\u200b\u200b\u200b\u200b\u200b\u200bThe 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 \u2014 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\u2019s disease and other brain disorders.<\/p>\n
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.\u00a0<\/p>\n
New stem cell-based research from UCLA, just published in Cell Reports<\/a>, 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.<\/p>\n 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.<\/p>\n Different brain regions, different problems<\/p>\n 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.<\/p>\n 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 \u2014 the brain\u2019s traffic cops that regulate neural activity.<\/p>\n These findings may help explain why patients with epilepsy often struggle with symptoms beyond seizures.\u00a0<\/p>\n \u201cSeizures are what bring families to the clinic, but for many parents, the bigger daily struggles are the other symptoms \u2014 problems with learning, behavior and sleep,\u201d said Dr. Ranmal Samarasinghe, co-senior author and clinical neurologist at UCLA. \u201cWhat we found is that these cognitive problems aren\u2019t just side effects of seizures. They likely arise from distinct disruptions in the hippocampus itself.\u201d<\/p>\n Understanding these hippocampal disruptions is the first step toward identifying treatments that can help with the full range of symptoms, Samarasinghe added.<\/p>\n Validating the model against human disease<\/p>\n 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\u2019 hippocampi\u00a0as well as regions unaffected by seizures. Abnormal brain rhythms appeared in both the patients\u2019 seizure \u201chot spots\u201d and in assembloids carrying SCN8A variants. In contrast, seizure-free brain regions and assembloids without the variants showed normal activity.<\/p>\n<\/p>\n \u201cThat was an important moment,\u201d 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<\/a> and the Intellectual and Developmental Disability Research Center at UCLA.<\/a>\u00a0\u201cIt showed us that the disease processes we see in stem cell models mirror what happens in patients.\u201d<\/p>\n 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.\u00a0<\/p>\n 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.<\/p>\n The technique could prove valuable for studying autism, schizophrenia and Alzheimer\u2019s disease \u2014 all conditions where hippocampal function plays a crucial role.<\/p>\n \u201cThis is a foothold into a whole new area of research,\u201d 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. \u201cWe 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.\u201d<\/p>\n The importance of sustained NIH funding<\/p>\n While the study highlights a major advance in modeling human brain circuits, the researchers cautioned that continued progress depends on stable federal research support.<\/p>\n \u201cIn my case, 100% of my NIH funding was suspended,\u201d Samarasinghe said. \u201cWithout that support, we\u2019ve 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.\u201d<\/p>\n Novitch added that the stop-and-start funding climate has left labs caught between tremendous new capabilities and the inability to fully use them.\u00a0<\/p>\n \u201cWe\u2019re able to create human brain-like specimens that finally allow us to probe the underlying causes of disease,\u201d he said. \u201cThis is a goldmine for understanding epilepsy, autism, Alzheimer\u2019s and other conditions \u2014 but we\u2019re being impeded from taking advantage of what\u2019s now technically possible.\u201d<\/p>\n Both scientists stressed that the stakes go beyond academic progress.\u00a0<\/p>\n \u201cFamilies come to us desperate for better options,\u201d Samarasinghe said. \u201cWithout NIH funding, we can\u2019t push forward the kinds of discoveries that could one day ease the daily struggles of children with epilepsy and related disorders. These delays don\u2019t just set back science \u2014 they prolong suffering.\u201d<\/p>\n 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.<\/p>\n","protected":false},"excerpt":{"rendered":"Key TakeawaysUCLA researchers used patient-derived stem cells to model how gene variants that cause developmental and epileptic encephalopathy…\n","protected":false},"author":2,"featured_media":143470,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[50],"tags":[200,79],"class_list":["post-143469","post","type-post","status-publish","format-standard","has-post-thumbnail","category-genetics","tag-genetics","tag-science"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/posts\/143469","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/comments?post=143469"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/posts\/143469\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/media\/143470"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/media?parent=143469"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/categories?post=143469"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/tags?post=143469"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}