# Utilizing Human Brain Organoids to Model the Differential Effects of SCN8A Mutation on Cortex and Hippocampus

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $237,822

## Abstract

Project Summary/Abstract
Epilepsy is a severe and debilitating disease and a significant public health concern. Epilepsy is also a
disease without a medical cure, and a disease where about 1 in 3 patients fails to respond to anti-seizure
medications. In the most severe epilepsy syndromes of childhood, medical control of seizures can be even
more challenging. Novel experimental platforms have the potential to play a critical role in advancing our
understanding and treatment of epilepsy. Brain organoids derived from human embryonic or induced
pluripotent stem cells are one such novel technology that has enormous potential. This is particularly true for
severe childhood epilepsies, as organoids are ideally suited to model early neural development. Organoids are
3D structures that recapitulate complex elements of human brain such as its laminar organization and cell
types seen in all six layers of human cortex. Since they can be human induced-pluripotent stem cell (hiPSC)
derived, an organoid can be produced directly from patient tissue. Recent advances in organoid technology
have resulted in the ability to generate distinct brain region-like organoids such as forebrain cortex and
hippocampus and to make “fusion” structures with integration of inhibitory and excitatory cell types.
 In the following proposal I will leverage these advances and build on an organoid platform that I have
recently developed to model brain circuit formation and dysfunction in epilepsy. Previously, l was able to
recapitulate hyperexcitable electrographic features in organoids derived from a patient with Rett syndrome, a
neurological disorder highly associated with seizures and epilepsy. I have now generated cortical and
hippocampal organoids from hiPSCs harboring mutations in the SCN8A gene. This mutation results in a
severe childhood epilepsy. I have found that the SCN8A mutant cortex organoids have a highly hyperexcitable
pattern of physiological activity compared to controls, whereas the SCN8A mutant hippocampus lacks a
particular type of neural oscillation that is important for memory consolidation called a sharp wave ripple. This
finding suggests that the SCN8A mutation results in different physiological activity patterns in distinct brain
regions. Based on published studies, I hypothesize that this difference is primarily due to dysfunction of
excitatory neurons in the cortex versus inhibitory interneurons in the hippocampus. I will now use an array of
techniques such as calcium indicator imaging, extracellular recordings, immunohistochemistry, and
manipulation of the genetic background of excitatory and inhibitory neurons within the organoid to test this
hypothesis. To increase the rigor and generalizability of my data, I will use hiPSC from three different patients
with pathogenic SCN8A mutations. Finally, I will perform drug testing to further isolate the role of specific cell
types to the observed phenotypes and for consideration as therapeutic agents in patients. ...

## Key facts

- **NIH application ID:** 10849727
- **Project number:** 5K08NS119747-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** RANMAL A SAMARASINGHE
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $237,822
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849727

## Citation

> US National Institutes of Health, RePORTER application 10849727, Utilizing Human Brain Organoids to Model the Differential Effects of SCN8A Mutation on Cortex and Hippocampus (5K08NS119747-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10849727. Licensed CC0.

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