Modeling Cortical Versus Hippocampal Network Dysfunction in a Human Brain Assembloid Model of Epilepsy and...

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Neurodevelopmental disorders impact multiple cognitive functions.
• Genetic epilepsy syndromes, like DEE-13, can cause seizures and memory deficits due to distinct brain region dysfunction.
• SCN8A gene mutations are implicated in DEE-13.

Purpose of the Study:

• To investigate how a single genetic disorder, DEE-13, differentially affects distinct brain regions.
• To model DEE-13 using patient-derived induced pluripotent stem cell (iPSC) assembloids.
• To establish a platform for studying neurodevelopmental disorders.

Main Methods:

• Utilized human patient iPSC-derived cortical and hippocampal-ganglionic eminence assembloids.
• Employed predictive computational modeling, immunohistochemistry, and single-nucleus RNA sequencing.
• Compared network hyperexcitability and neuron organization between cortical and hippocampal assembloids.

Main Results:

• Cortical assembloids exhibited network hyperexcitability, characteristic of epileptogenic tissue.
• Hippocampal assembloids did not show hyperexcitability but displayed dysregulation patterns similar to in vivo epilepsy patient data.
• Identified specific changes in excitatory and inhibitory neuron organization within hippocampal assembloids.

Conclusions:

• A single pathogenic variant (SCN8A mutation) has region-specific impacts on brain development and function.
• Hippocampal assembloids provide a valuable model for studying neurodevelopmental disorders affecting this brain region.
• Findings highlight the importance of region-specific modeling in understanding complex neurological conditions.