Synaptotagmin-11 mediates a vesicle trafficking pathway that is essential for development and synaptic plasticity
Synaptotagmin-11 mediates a vesicle trafficking pathway that is essential for development and synaptic plasticity
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DOI：
10.1101/gad.320077.118
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发表时间：
2019-03-01
影响因子：
10.5
通讯作者：
Maximov, Anton
中科院分区：
文献类型：
--
作者：
Shimojo, Masafumi;Madara, Joseph;Maximov, Anton
Synaptotagmin-11（Syt 11）是一种缺乏明显结合钙、磷脂或SNARE蛋白能力的Synaptotagmin同种型。虽然人类遗传学研究已经将Syt 11基因的突变与精神分裂症和帕金森病联系起来，但Syt 11的定位或生理作用仍不清楚。我们发现，在神经元中，Syt 11驻留在丰富的囊泡，不同于突触囊泡，类似于运输内体。这些囊泡通过质膜以活性依赖的方式再循环，但它们的胞吐作用缓慢且不稳定。缺乏Syt 11的组成型敲除小鼠在出生后不久死亡，这表明Syt 11介导的膜转运是生存所必需的。与此相反，选择性消融Syt 11兴奋性前脑神经元使用条件性敲除不影响寿命，但受损的突触可塑性和记忆。Syt 11缺陷的神经元显示正常分泌的快速神经递质和肽，但表现出减少的长期突触增强。因此，Syt 11是神经元囊泡运输途径的重要组成部分，不同于特征明确的突触囊泡运输途径，但也是生命所必需的。
Synaptotagmin-11 (Syt11) is a Synaptotagmin isoform that lacks an apparent ability to bind calcium, phospholipids, or SNARE proteins. While human genetic studies have linked mutations in the Syt11 gene to schizophrenia and Parkinson's disease, the localization or physiological role of Syt11 remain unclear. We found that in neurons, Syt11 resides on abundant vesicles that differ from synaptic vesicles and resemble trafficking endosomes. These vesicles recycle via the plasma membrane in an activity-dependent manner, but their exocytosis is slow and desynchronized. Constitutive knockout mice lacking Syt11 died shortly after birth, suggesting Syt11-mediated membrane transport is required for survival. In contrast, selective ablation of Syt11 in excitatory forebrain neurons using a conditional knockout did not affect life span but impaired synaptic plasticity and memory. Syt11-deficient neurons displayed normal secretion of fast neurotransmitters and peptides but exhibited a reduction of long-term synaptic potentiation. Hence, Syt11 is an essential component of a neuronal vesicular trafficking pathway that differs from the well-characterized synaptic vesicle trafficking pathway but is also essential for life.