Journal
BRAIN
Volume 145, Issue 6, Pages 1962-1977Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awab479
Keywords
focal cortical dysplasia; cortical organoids; cell adhesion; cell proliferation; neuronal network
Categories
Funding
- UCSD Stem Cell Program [AES2017SD1]
- [2013/07559-3]
- [2017/50404-1]
- [2019/09090-9]
- [2017/13220-0]
- [2018/02967-0]
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Research on human cortical organoids derived from patients with focal cortical dysplasia type II revealed characteristics such as impaired cell proliferation, presence of dysmorphic neurons and balloon cells, and neuronal network hyperexcitability. Additionally, alterations in cell structure and function were observed, leading to compromised neural network formation and cellular immaturity.
Focal cortical dysplasia is a highly epileptogenic cortical malformation with few treatment options. Here, we generated human cortical organoids from patients with focal cortical dysplasia type II. Using this human model, we mimicked some focal cortical dysplasia hallmarks, such as impaired cell proliferation, the presence of dysmorphic neurons and balloon cells, and neuronal network hyperexcitability. Furthermore, we observed alterations in the adherens junctions zonula occludens-1 and partitioning defective 3, reduced polarization of the actin cytoskeleton, and fewer synaptic puncta. Focal cortical dysplasia cortical organoids showed downregulation of the small GTPase RHOA, a finding that was confirmed in brain tissue resected from these patients. Functionally, both spontaneous and optogenetically- evoked electrical activity revealed hyperexcitability and enhanced network connectivity in focal cortical dysplasia organoids. Taken together, our findings suggest a ventricular zone instability in tissue cohesion of neuroepithelial cells, leading to a maturational arrest of progenitors or newborn neurons, which may predispose to cellular and functional immaturity and compromise the formation of neural networks in focal cortical dysplasia.
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