Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Periventricular heterotopia (PH) is a brain malformation linked to developmental delays and seizures.
• Understanding the neurophysiology of PH is crucial for developing effective treatments.
• Human cerebral organoids (hCOs) offer a model to study PH, but their neuronal activity was unexamined.

Purpose of the Study:

• To investigate the neuronal activity and cellular basis of PH using hCOs.
• To identify molecular and functional changes in neurons from PH models.
• To explore potential therapeutic targets for PH.

Main Methods:

• Generation of hCOs from patients with FAT4 or DCHS1 mutations.
• Silicon probe recordings to assess spontaneous neuronal activity.
• Transcriptome, proteome, and patch-clamp analyses to examine cellular and synaptic function.
• Morphological analysis of neurons.

Main Results:

• FAT4 and DCHS1 hCOs exhibited exaggerated spontaneous neuronal firing.
• Transcriptome and proteome data indicated altered neuronal morphology and synaptic function.
• DCHS1 neurons showed a reduced spike threshold, linked to increased sodium channels.
• PH neurons displayed increased morphological complexity and synaptic alterations causing hyperactivity.
• Wild-type DCHS1 expression rescued hyperactivity in DCHS1 neurons.

Conclusions:

• hCOs accurately model PH-associated neuronal hyperactivity.
• Altered neuronal morphology, synaptic function, and ion channel expression contribute to PH pathophysiology.
• These findings provide critical insights into the cellular mechanisms underlying gray matter heterotopia.