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[This article belongs to Volume - 69, Issue - 9]
Published on : 2024-09-05 12:39:09
Article Code: AMJ-05-09-2024-12297
Title : Patient-Derived Cortical Organoids from Ischemic Stroke Surrogates Reveal Neuronal Excitotoxicity Mechanisms Mediated by GRIN2B Glutamate Receptor Variants
Author(s) : Dr. Isabella Romano
Abstract :
The molecular determinants of selective neuronal vulnerability in acute ischemic stroke remain poorly characterized.
We established patient-derived cortical organoids from fibroblasts of stroke survivors with extreme phenotypes
(large infarct volume versus small lesion size) and subjected them to oxygen-glucose deprivation (OGD). Organoids
derived from high-vulnerability patients exhibited exaggerated calcium influx and delayed neuronal death following
OGD. Whole-exome sequencing identified rare deleterious variants in GRIN2B encoding the GluN2B NMDA receptor
subunit. CRISPR-Cas9 correction of the GRIN2B variant in patient iPSCs normalized calcium responses and conferred
resistance to excitotoxicity. Pharmacological blockade with ifenprodil, a GluN2B-selective antagonist, rescued
viability in susceptible organoids. This precision medicine model identifies GRIN2B as a pharmacogenomic
determinant of stroke outcome and validates organoid platforms for cerebrovascular disease modeling.