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.

Dynamin-1 是一种大型 GTP 酶，在哺乳动物神经末梢突触小泡内吞作用中发挥重要作用。 dynamin-1 基因 ( DNM1 ) 中的杂合错义突变会导致一种新型癫痫性脑病，致病性突变聚集在其必需 GTP 酶活性所需的区域内。我们揭示了最常见的致病性DNM1突变 R237W，当在中枢神经元中过度表达时，会破坏 dynamin-1 酶活性和内吞作用。为了确定这种突变如何影响细胞、回路和行为功能，我们培育了一只携带 R237W 突变的小鼠。杂合子小鼠的神经元除了兴奋性神经传递改变和癫痫样表型外，还表现出内吞作用功能障碍。重要的是，这些表型可以通过药物 BMS-204352 在细胞、回路和体内水平上得到纠正，从而加速内吞作用。在这里，我们证明了功能失调的内吞作用和癫痫性脑病之间存在可靠的联系，并且重要的是揭示了突触小泡回收可能是单基因难治性癫痫的可行治疗靶点。