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

Lookup NU author(s): Professor Matthias TrostORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2023, Springer Nature Limited.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.

Publication metadata

Author(s): Bonnycastle K, Dobson KL, Blumrich E-M, Gajbhiye A, Davenport EC, Pronot M, Steinruecke M, Trost M, Gonzalez-Sulser A, Cousin MA

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2023

Volume: 14

Issue: 1

Online publication date: 30/08/2023

Acceptance date: 17/08/2023

Date deposited: 27/09/2023

ISSN (electronic): 2041-1723

Publisher: Nature Research

URL: https://doi.org/10.1038/s41467-023-41035-w

DOI: 10.1038/s41467-023-41035-w

PubMed id: 37648685

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