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Overcoming presynaptic effects of VAMP2 mutations with 4‐aminopyridine treatment
Author(s) -
Simmons Roxanne L.,
Li Haiyan,
Alten Baris,
Santos Magda S.,
Jiang Ruiji,
Paul Brianna,
Lalani Sanam J.,
Cortesi Audrey,
Parks Kendall,
Khandelwal Nitin,
SmithPackard Bethany,
Phoong Malay A.,
Chez Michael,
Fisher Heather,
Scheuerle Angela E.,
Shinawi Marwan,
Hussain Shaun A.,
Kavalali Ege T.,
Sherr Elliott H.,
Voglmaier Susan M.
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24109
Subject(s) - 4 aminopyridine , biology , neurotransmission , synaptic vesicle , exocytosis , synapse , neuroscience , genetics , potassium channel , endocrinology , receptor , vesicle , secretion , membrane
Clinical and genetic features of five unrelated patients with de novo pathogenic variants in the synaptic vesicle‐associated membrane protein 2 (VAMP2) reveal common features of global developmental delay, autistic tendencies, behavioral disturbances, and a higher propensity to develop epilepsy. For one patient, a cognitively impaired adolescent with a de novo stop‐gain VAMP2 mutation, we tested a potential treatment strategy, enhancing neurotransmission by prolonging action potentials with the aminopyridine family of potassium channel blockers, 4‐aminopyridine and 3,4‐diaminopyridine, in vitro and in vivo. Synaptic vesicle recycling and neurotransmission were assayed in neurons expressing three VAMP2 variants by live‐cell imaging and electrophysiology. In cellular models, two variants decrease both the rate of exocytosis and the number of synaptic vesicles released from the recycling pool, compared with wild‐type. Aminopyridine treatment increases the rate and extent of exocytosis and total synaptic charge transfer and desynchronizes GABA release. The clinical response of the patient to 2 years of off‐label aminopyridine treatment includes improved emotional and behavioral regulation by parental report, and objective improvement in standardized cognitive measures. Aminopyridine treatment may extend to patients with pathogenic variants in VAMP2 and other genes influencing presynaptic function or GABAergic tone, and tested in vitro before treatment.