Bonrath, R. | Search bioRxiv

bioRxiv2024

Neuronal Hyperactivity in Neurons Derived from Individuals with Grey Matter Heterotopia

Periventricular heterotopia (PH), a common form of grey matter heterotopia associated with developmental delay and drug-resistant seizures, poses a challenge in understanding its neurophysiological basis. Human cerebral organoids (hCOs) derived from patients with causative mutations in FAT4 or DCHS1 mimic PH features. However, neuronal activity in these 3D models has not yet been invetigated. Here, silicon probe recordings revealed exaggerated spontaneous spike activity in FAT4 and DCHS1 hCOs, suggesting functional changes in neuronal networks. Transcriptome and proteome analyses identified changes in gene ontology terms associated with neuronal morphology and synaptic function. Furthermore, patch-clamp recordings revealed a decreased spike threshold specifically in DCHS1 neurons, likely due to increased somatic voltage-gated sodium channels. Morphological reconstructions and immunostainings revealed greater morphological complexity of PH neurons and synaptic alterations contributing to hyperactivity, with morphological rescue observed in DCHS1 neurons by wild-type DCHS1 expression. Overall, we provide new comprehensive insights into the cellular changes underlying symptoms of grey matter heterotopia.

neuroscience↗

bioRxiv2022

Extrinsic regulation of interneuron specification and migration

The imbalance between excitatory and inhibitory neurons in the human brain might lead to neurodevelopmental and neuropsychiatric disorders including cortical malformations, epilepsy, and autism spectrum disorders. We propose that the extracellular environment regulates interneuron differentiation and migration during development, ultimately affecting the excitatory/inhibitory balance. Using ventral cerebral organoids and dorso-ventral cerebral assembloids with mutations in the extracellular matrix gene LGALS3BP, we show that the composition of the extracellular environment regulates the molecular differentiation of neurons, resulting in alterations in migratory dynamics. To investigate how the extracellular environment affects neuronal specification and migration, we characterized the protein content of extracellular vesicles from cerebral organoids carrying a mutation in LGALS3BP, previously identified in individuals with cortical malformations and neuropsychiatric disorders. These results revealed differences in protein composition. Interestingly, proteins associated with cell-fate decision, neuronal migration and extracellular matrix composition were altered in mutant extracellular vesicles. Moreover, we show that treatment with extracellular vesicles changes the transcriptomic profile in neural progenitor cells. Our results indicate that neuronal molecular differentiation is regulated by factors released into the extracellular environment.

developmental biology↗