Human BDNF/TrkB variants impair hippocampal synaptogenesis and associate with neurobehavioural abnormalities.
Human BDNF/TrkB variants impair hippocampal synaptogenesis and associate with neurobehavioural abnormalities.
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人类 BDNF/TrkB 变异会损害海马突触发生并与神经行为异常相关。
DOI：
10.1038/s41598-020-65531-x
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发表时间：
2020
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
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作者：
Sonoyama,Takuhiro;Stadler,LukasKJ;Zhu,Mingyan;Keogh,JuliaM;Henning,Elana;Hisama,Fuki;Kirwan,Peter;Jura,Magdalena;Blaszczyk,BeataK;DeWitt,DavidC;Brouwers,Bas;Hyvönen,Marko;Barroso,Inês;Merkle,FlorianT;Appleyard,SuzanneM;
脑源性神经营养因子（BDNF）通过其高亲和力受体原肌球蛋白受体激酶B（TrkB）来调节神经元的发育、突触形成和可塑性。在啮齿类动物中，BdnfandTrkB的遗传破坏导致体重增加和一系列神经行为表型。在此，我们在一个儿童期发病的严重肥胖人群中，对BDNF的一种新的错义变异和TrkB的七种罕见变异进行了功能性鉴定。在细胞中，E183 K BDNF变体导致成熟肽的加工和分泌受损。TrkB激酶结构域的多个变异体和胞外结构域的一个变异体通过多种信号传导途径导致功能丧失，损害神经突生长，并显著抑制海马神经元的突触发生。BDNF/TrkB变异体携带者表现出学习困难、记忆受损、多动、刻板，有时表现出适应不良行为。总之，人类BDNF/TrkB变体功能的丧失损害海马突触发生可能导致一系列神经行为障碍。
Brain-derived neurotrophic factor (BDNF) signals through its high affinity receptor Tropomyosin receptor kinase-B (TrkB) to regulate neuronal development, synapse formation and plasticity. In rodents, genetic disruption ofBdnfandTrkBleads to weight gain and a spectrum of neurobehavioural phenotypes. Here, we functionally characterised ade novomissense variant inBDNFand seven rare variants inTrkBidentified in a large cohort of people with severe, childhood-onset obesity. In cells, the E183K BDNF variant resulted in impaired processing and secretion of the mature peptide. Multiple variants in the kinase domain and one variant in the extracellular domain of TrkB led to a loss of function through multiple signalling pathways, impaired neurite outgrowth and dominantly inhibited glutamatergic synaptogenesis in hippocampal neurons.BDNF/TrkBvariant carriers exhibited learning difficulties, impaired memory, hyperactivity, stereotyped and sometimes, maladaptive behaviours. In conclusion, human loss of functionBDNF/TrkBvariants that impair hippocampal synaptogenesis may contribute to a spectrum of neurobehavioural disorders.