State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences and Peking Union Medical College, Neuroscience Center, Chinese Academy of Medical Sciences, 100005 Beijing, China.
Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31438-31447. doi: 10.1073/pnas.2016416117. Epub 2020 Nov 23.
Synaptotagmin-7 (Syt7) probably plays an important role in bipolar-like behavioral abnormalities in mice; however, the underlying mechanisms for this have remained elusive. Unlike antidepressants that cause mood overcorrection in bipolar depression, -methyl-d-aspartate receptor (NMDAR)-targeted drugs show moderate clinical efficacy, for unexplained reasons. Here we identified Syt7 single nucleotide polymorphisms (SNPs) in patients with bipolar disorder and demonstrated that mice lacking Syt7 or expressing the SNPs showed GluN2B-NMDAR dysfunction, leading to antidepressant behavioral consequences and avoidance of overcorrection by NMDAR antagonists. In human induced pluripotent stem cell (iPSC)-derived and mouse hippocampal neurons, Syt7 and GluN2B-NMDARs were localized to the peripheral synaptic region, and Syt7 triggered multiple forms of glutamate release to efficiently activate the juxtaposed GluN2B-NMDARs. Thus, while Syt7 deficiency and SNPs induced GluN2B-NMDAR dysfunction in mice, patient iPSC-derived neurons showed Syt7 deficit-induced GluN2B-NMDAR hypoactivity that was rescued by Syt7 overexpression. Therefore, Syt7 deficits induced mania-like behaviors in mice by attenuating GluN2B activity, which enabled NMDAR antagonists to avoid mood overcorrection.
突触结合蛋白 7（Syt7）可能在小鼠双相样行为异常中发挥重要作用；然而，其潜在机制仍不清楚。与导致双相抑郁情绪过度矫正的抗抑郁药不同， - 甲基 - D - 天冬氨酸受体（NMDAR）靶向药物显示出适度的临床疗效，但原因尚不清楚。在这里，我们在双相情感障碍患者中鉴定出 Syt7 单核苷酸多态性（SNP），并证明缺乏 Syt7 或表达 SNP 的小鼠表现出 GluN2B-NMDAR 功能障碍，导致抗抑郁行为后果，并避免 NMDAR 拮抗剂的过度矫正。在人类诱导多能干细胞（iPSC）衍生和小鼠海马神经元中，Syt7 和 GluN2B-NMDAR 定位于周围突触区，Syt7 触发多种形式的谷氨酸释放，以有效地激活相邻的 GluN2B-NMDAR。因此，虽然 Syt7 缺失和 SNP 诱导小鼠 GluN2B-NMDAR 功能障碍，但患者 iPSC 衍生神经元表现出 Syt7 缺乏诱导的 GluN2B-NMDAR 低活性，Syt7 过表达可挽救这种低活性。因此，Syt7 缺乏通过减弱 GluN2B 活性导致小鼠出现躁狂样行为，这使得 NMDAR 拮抗剂能够避免情绪过度矫正。
