Good news!
"Key takeaways
- ... 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.
...
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. ..."
From the highlights and abstract:
"Highlights
• Cortical assembloids with SCN8A mutations exhibit marked network hyperexcitability
• Hippocampal assembloids show theta-gamma coupling deficits, mirroring patient recordings
• Computational modeling predicts selective O-LM interneuron loss in the hippocampus
• scRNAseq and IHC reveal region-specific neuronal identity changes in DEE-13 assembloids
Summary
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."
Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability (open access)
Graphical abstract
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