Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy

Katherine Bonnycastle (), Katharine L. Dobson, Eva-Maria Blumrich, Akshada Gajbhiye, Elizabeth C. Davenport, Marie Pronot, Moritz Steinruecke, Matthias Trost, Alfredo Gonzalez-Sulser and Michael A. Cousin ()
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Katherine Bonnycastle: University of Edinburgh
Katharine L. Dobson: University of Edinburgh
Eva-Maria Blumrich: University of Edinburgh
Akshada Gajbhiye: Faculty of Medical Sciences
Elizabeth C. Davenport: University of Edinburgh
Marie Pronot: University of Edinburgh
Moritz Steinruecke: University of Edinburgh
Matthias Trost: Faculty of Medical Sciences
Alfredo Gonzalez-Sulser: University of Edinburgh
Michael A. Cousin: University of Edinburgh

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41035-w

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