Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature communications, 2023-08, Vol.14 (1), p.5285-5285, Article 5285

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. One third of all epilepsies are treatment-resistant. Here, the authors show in a genetic model of epilepsy that a repurposed drug can correct cell defects, brain circuits and seizure-like events by accelerating endocytosis.