Junctional instability in neuroepithelium and network hyperexcitability in a focal cortical dysplasia human model.
cell adhesion
cell proliferation
cortical organoids
focal cortical dysplasia
neuronal network
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
30 06 2022
30 06 2022
Historique:
received:
30
07
2021
revised:
15
10
2021
accepted:
19
11
2021
pubmed:
28
12
2021
medline:
6
7
2022
entrez:
27
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34957478
pii: 6484506
doi: 10.1093/brain/awab479
pmc: PMC9336577
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1962-1977Subventions
Organisme : NINDS NIH HHS
ID : P30 NS047101
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.
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