Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Straße 10, 13125 Berlin, Germany.
NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Virchowweg 6, 10117 Berlin, Germany.
Neuron. 2015 Oct 21;88(2):330-44. doi: 10.1016/j.neuron.2015.08.034. Epub 2015 Sep 24.
Neurotransmission depends on synaptic vesicle (SV) exocytosis driven by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation of vesicular synaptobrevin/VAMP2 (Syb2). Exocytic fusion is followed by endocytic SV membrane retrieval and the high-fidelity reformation of SVs. Syb2 is the most abundant SV protein with 70 copies per SV, yet, one to three Syb2 molecules appear to be sufficient for basal exocytosis. Here we demonstrate that loss of the Syb2-specific endocytic adaptor AP180 causes a moderate activity-dependent reduction of vesicular Syb2 levels, defects in SV reformation, and a corresponding impairment of neurotransmission that lead to excitatory/inhibitory imbalance, epileptic seizures, and premature death. Further reduction of Syb2 levels in AP180(-/-)/Syb2(+/-) mice results in perinatal lethality, whereas Syb2(+/-) mice partially phenocopy loss of AP180, indicating that reduced vesicular Syb2 levels underlie the observed defects in neurotransmission. Thus, a large vesicular Syb2 pool maintained by AP180 is crucial to sustain efficient neurotransmission and SV reformation.
神经递质传递依赖于突触小泡（SV）的胞吐作用，该作用由可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）复合物的形成驱动，其中包含囊泡突触融合蛋白/VAMP2（Syb2）。胞吐作用之后是 SV 膜的内吞回收和 SV 的高保真重构。Syb2 是 SV 中含量最丰富的蛋白，每个 SV 中有 70 个拷贝，但一个到三个 Syb2 分子似乎足以维持基础的胞吐作用。在这里，我们证明了 Syb2 特异性内吞衔接蛋白 AP180 的缺失会导致囊泡 Syb2 水平的适度活性依赖性降低、SV 重构缺陷以及相应的神经递质传递损伤，从而导致兴奋性/抑制性失衡、癫痫发作和过早死亡。在 AP180(-/-)/Syb2(+/-) 小鼠中进一步降低 Syb2 水平会导致围产期致死，而 Syb2(+/-) 小鼠部分模拟了 AP180 的缺失，表明囊泡 Syb2 水平降低是观察到的神经递质传递缺陷的基础。因此，AP180 维持的大量囊泡 Syb2 池对于维持有效的神经递质传递和 SV 重构至关重要。
