1. Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy.
- Author
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Bonnycastle K, Dobson KL, Blumrich EM, Gajbhiye A, Davenport EC, Pronot M, Steinruecke M, Trost M, Gonzalez-Sulser A, and Cousin MA
- Subjects
- Animals, Mice, Seizures genetics, Disease Models, Animal, Biological Transport, Mammals, Dynamin I genetics, Drug Resistant Epilepsy
- Abstract
Dynamin-1 is a large GTPase with an obligatory role in synaptic vesicle endocytosis at mammalian nerve terminals. Heterozygous missense mutations in the dynamin-1 gene (DNM1) cause a novel form of epileptic encephalopathy, with pathogenic mutations clustering within regions required for its essential GTPase activity. We reveal the most prevalent pathogenic DNM1 mutation, R237W, disrupts dynamin-1 enzyme activity and endocytosis when overexpressed in central neurons. To determine how this mutation impacted cell, circuit and behavioural function, we generated a mouse carrying the R237W mutation. Neurons from heterozygous mice display dysfunctional endocytosis, in addition to altered excitatory neurotransmission and seizure-like phenotypes. Importantly, these phenotypes are corrected at the cell, circuit and in vivo level by the drug, BMS-204352, which accelerates endocytosis. Here, we demonstrate a credible link between dysfunctional endocytosis and epileptic encephalopathy, and importantly reveal that synaptic vesicle recycling may be a viable therapeutic target for monogenic intractable epilepsies., (© 2023. Springer Nature Limited.)
- Published
- 2023
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