Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability

Affiliations

¹ Department of Neurology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
² Department of Neurology, University of California, Davis, School of Medicine, Sacramento, CA 95817, USA; Center for Mind and Brain, University of California, Davis, Davis, CA 95618, USA.
³ Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA.
⁴ Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA; Department of Neurological Surgery, University of California, Davis, School of Medicine, Sacramento, CA 95817, USA.
⁶ Department of Electrical Engineering, Sapientia Hungarian University of Transylvania, Târgu-Mureş/Corunca 540485, Romania.
⁷ Department of Neurology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA; Department of Physiology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
⁸ Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual Development and Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: bnovitch@g.ucla.edu.
⁹ Department of Neurology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA; Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual Development and Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: rsamarasinghe@mednet.ucla.edu.

PMID: 40925365
DOI: 10.1016/j.celrep.2025.116217

Free article

Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability

Colin M McCrimmon et al. Cell Rep. 2025.

Free article

. 2025 Sep 23;44(9):116217.

doi: 10.1016/j.celrep.2025.116217. Epub 2025 Sep 8.

Authors

Affiliations

¹ Department of Neurology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
² Department of Neurology, University of California, Davis, School of Medicine, Sacramento, CA 95817, USA; Center for Mind and Brain, University of California, Davis, Davis, CA 95618, USA.
³ Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA.
⁴ Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA; Department of Neurological Surgery, University of California, Davis, School of Medicine, Sacramento, CA 95817, USA.
⁶ Department of Electrical Engineering, Sapientia Hungarian University of Transylvania, Târgu-Mureş/Corunca 540485, Romania.
⁷ Department of Neurology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA; Department of Physiology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
⁸ Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual Development and Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: bnovitch@g.ucla.edu.
⁹ Department of Neurology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA; Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual Development and Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: rsamarasinghe@mednet.ucla.edu.

PMID: 40925365
DOI: 10.1016/j.celrep.2025.116217

Abstract

Neurodevelopmental disorders often impair multiple cognitive domains. For instance, a genetic epilepsy syndrome might cause seizures due to cortical hyperexcitability and present with memory impairments arising from hippocampal dysfunction. This study examines how a single disorder differentially affects distinct brain regions using induced pluripotent stem cell (iPSC)-derived cortical- and hippocampal-ganglionic eminence assembloids to model developmental and epileptic encephalopathy 13, a condition arising from gain-of-function mutations in the SCN8A gene encoding the sodium channel Nav1.6. While cortical assembloids showed network hyperexcitability akin to epileptogenic tissue, hippocampal assembloids did not, and instead displayed network dysregulation patterns similar to in vivo hippocampal recordings from epilepsy patients. Predictive computational modeling, immunohistochemistry, and single-nucleus RNA sequencing revealed changes in excitatory and inhibitory neuron organization that were specific to hippocampal assembloids. These findings highlight the unique impacts of a single pathogenic variant across brain regions and establish hippocampal assembloids as a platform for studying neurodevelopmental disorders.

Keywords: CP: Neuroscience; brain organoids; cellular neuroscience; disease modeling; epilepsy; hippocampal assembloids; neural circuits; neural stem cells.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

Modeling Cortical Versus Hippocampal Network Dysfunction in a Human Brain Assembloid Model of Epilepsy and Intellectual Disability.
McCrimmon CM, Toker D, Pahos M, Lozano K, Lin JJ, Parent J, Tidball A, Zheng J, Molnár L, Mody I, Novitch BG, Samarasinghe RA. McCrimmon CM, et al. bioRxiv [Preprint]. 2024 Sep 8:2024.09.07.611739. doi: 10.1101/2024.09.07.611739. bioRxiv. 2024. Update in: Cell Rep. 2025 Sep 23;44(9):116217. doi: 10.1016/j.celrep.2025.116217. PMID: 39282353 Free PMC article. Updated. Preprint.

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

LinkOut - more resources

Full Text Sources
- Elsevier Science
Medical
- MedlinePlus Consumer Health Information
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability

Affiliations

Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous