Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1epileptic encephalopathy

Katherine Bonnycastle, Katharine L Dobson, Eva-Maria Blumrich, Akshada Gajbhiye, Elizabeth C Davenport, Marie Pronot, Moritz Steinruecke, Matthias Trost, Alfredo Gonzalez-Sulser, Michael A Cousin

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)1-19
JournalNature Communications
Publication statusPublished - 30 Aug 2023


Dive into the research topics of 'Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1epileptic encephalopathy'. Together they form a unique fingerprint.

Cite this