Genetics 2024 May 24; doi: 10.1093/genetics/iyae085.

Knockdown of NeuroD2 leads to seizure-like behaviour, brain neuronal hyperactivity and a leaky blood-brain barrier in a Xenopus laevis tadpole model of DEE75.

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Developmental and Epileptic Encephalopathies (DEE) are a genetically diverse group of severe, early onset seizure disorders. DEE are normally identified clinically in the first six months of life by the presence of frequent, difficult to control seizures and accompanying stalling or regression of development. DEE75 results from de novo mutations of the NEUROD2 gene that result in loss of activity of the encoded transcription factor, and the seizure phenotype was shown to be recapitulated in Xenopus tropicalis tadpoles. We used CRISPR/Cas9 to make a DEE75 model in Xenopus laevis, to further investigate the developmental aetiology. NeuroD2.S CRISPR/Cas9 edited tadpoles were more active, swam faster on average, and had more seizures (C-shaped contractions resembling unprovoked C-start escape responses) than their sibling controls. Live imaging of Ca2+ signalling revealed prolongued, strong signals sweeping through the brain, indicative of neuronal hyperactivity. While the resulting tadpole brain appeared grossly normal, the blood-brain barrier was found to be leakier than that of controls. Additionally, the TGFβ antagonist Losartan was shown to have a short-term protective effect, reducing neuronal hyperactivity and reducing permeability of the blood-brain barrier. Treatment of NeuroD2 CRISPant tadpoles with 5 mM Losartan decreased seizure events by more than fourfold compared to the baseline. Our results support a model of DEE75 resulting from reduced NeuroD2 activity during vertebrate brain development, and indicate that a leaky blood-brain barrier contributes to epileptogenesis.

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Species referenced: Xenopus tropicalis Xenopus laevis
Genes referenced: neurod2 tgfb1

???displayArticle.disOnts??? developmental and epileptic encephalopathy 75 [+]
???displayArticle.omims??? DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 75; DEE75