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Neuronal Hyperactivity in Neurons Derived from Individuals with Grey Matter Heterotopia

ABSTRACT: Periventricular heterotopia (PH), the most common form of grey matter heterotopia, represents a cortical malformation that is often associated with developmental delay and drug-resistant seizures1,2. The detailed neurophysiological underpinnings of PH symptoms in humans remain, however, elusive. Human cerebral organoids (hCOs) derived from patients with causative mutations in FAT4 or DCHS1 exhibit key features of PH3, but neuronal activity in these 3D models has not yet been investigated. Here, using silicon probe recordings, we detected exaggerated spontaneous spike activity in FAT4 and DCHS1 hCOs, suggesting functional changes in neuronal networks. Patch-clamp recordings revealed a decreased spike threshold exclusively for DCHS1 neurons, which presumably results from an enhanced density of somatic voltage-gated sodium channels. Furthermore, single-cell morphological reconstructions and immunostainings demonstrated greater morphological complexity of neurons and synaptic alterations, rather than an imbalance of excitatory-inhibitory neuron number, as contributing to the hyperactivity observed in FAT4 and DCHS1 hCOs. The morphological phenotype was rescued by an expression of wild-type DCHS1 in DCHS1 neurons. In addition, transcriptome and proteome analyses uncovered changes in GO terms associated with neuronal morphology and synaptic function. Overall, we provide detailed new insights into cellular alterations likely contributing to the emergence of symptoms in grey matter heterotopia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220673 | GEO | 2025/01/02

REPOSITORIES: GEO

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Project description:Increasing evidence indicates heterogeneity in functional and molecular properties of oligodendrocyte lineage cells both during development and under pathologic conditions. In multiple sclerosis, remyelination of grey matter lesions exceeds that in white matter. Here we used cells derived from grey matter versus white matter regions of surgically resected human brain tissue samples, to compare the capacities of human A2B5-positive progenitor cells and mature oligodendrocytes to ensheath synthetic nanofibers, and relate differences to the molecular profiles of these cells. For both cell types, the percentage of ensheathing cells was greater for grey matter versus white matter cells. For both grey matter and white matter samples, the percentage of cells ensheathing nanofibers was greater for A2B5-positive cells versus mature oligodendrocytes. Grey matter A2B5-positive cells were more susceptible than white matter A2B5-positive cells to injury induced by metabolic insults. Bulk RNA sequencing indicated that separation by cell type (A2B5-positive vs mature oligodendrocytes) is more significant than by region but segregation for each cell type by region is apparent. Molecular features of grey matter versus white matter derived A2B5-positive and mature oligodendrocytes were lower expression of mature oligodendrocyte genes and increased expression of early oligodendrocyte lineage genes. Genes and pathways with increased expression in grey matter derived cells with relevance for myelination included those related to responses to external environment, cell-cell communication, cell migration, and cell adhesion. Immune and cell death related genes were up-regulated in grey matter derived cells. We observed a significant number of up-regulated genes shared between the stress/injury and myelination processes, providing a basis for these features. In contrast to oligodendrocyte lineage cells, no functional or molecular heterogeneity was detected in microglia maintained in vitro, likely reflecting the plasticity of these cells ex vivo. The combined functional and molecular data indicate that grey matter human oligodendrocytes have increased intrinsic capacity to myelinate but also increased injury susceptibility, in part reflecting their being at a stage earlier in the oligodendrocyte lineage.

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Neuronal Hyperactivity in Neurons Derived from Individuals with Grey Matter Heterotopia

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