Synaptotagmin-7 deficiency induces mania-like behavioral abnormalities through attenuating GluN2B activity
Synaptotagmin-7 deficiency induces mania-like behavioral abnormalities through attenuating GluN2B activity
复制标题
Synaptotagmin-7 缺陷通过减弱 GluN2B 活性诱导躁狂样行为异常
DOI：
10.1073/pnas.2016416117
复制
发表时间：
2020-11
影响因子：
11.1
通讯作者：
Jun Yao
中科院分区：
文献类型：
--
作者：
Qiu-Wen Wang;Si-Yao Lu;Yao-Nan Liu;Hui Wei;Yun Chen;Wei Shen;Yan-Fen Chen;Chong-Lei Fu;Ying-Han Wang;Anbang Dai;Xuan Huang;Fred H. Gage;Qi Xu;Jun Yao
虽然synaptotagmin-7（Syt 7）已被发现在小鼠双极样行为异常中发挥重要作用，但异常行为背后的分子机制仍不清楚。N-甲基-d-天冬氨酸受体（NMDAR）拮抗剂（如氯胺酮）在治疗双相抑郁症中具有良好疗效的原因也尚不清楚。在本研究中，我们证明了在人类诱导多能干细胞衍生的和小鼠海马神经元中，Syt 7触发了外周活性区中的谷氨酸释放，这有效地激活了并置的突触后GluN 2B-NMDAR。由于Syt 7缺陷，GluN 2B-NMDAR变得活性低下，因此产生抗抑郁作用，这在动物中诱导躁狂样行为异常。Synaptotagmin-7（Syt 7）可能在小鼠双极样行为异常中起重要作用;然而，其潜在机制仍然难以捉摸。与导致双相抑郁症情绪过度矫正的抗抑郁药不同，N-甲基-d-天冬氨酸受体（NMDAR）靶向药物显示出中等的临床疗效，原因不明。在这里，我们确定了双相情感障碍患者的Syt 7单核苷酸多态性（SNP），并证明缺乏Syt 7或表达SNP的小鼠显示GluN 2B-NMDAR功能障碍，导致抗抑郁行为后果和避免NMDAR拮抗剂的过度矫正。在人类诱导多能干细胞（iPSC）衍生的和小鼠海马神经元中，Syt 7和GluN 2B-NMDAR定位于外周突触区域，Syt 7触发多种形式的谷氨酸释放，以有效激活并列的GluN 2B-NMDAR。因此，虽然Syt 7缺陷和SNP在小鼠中诱导GluN 2B-NMDAR功能障碍，但患者iPSC衍生的神经元显示Syt 7缺陷诱导的GluN 2B-NMDAR活性低下，其被Syt 7过表达挽救。因此，Syt 7缺陷通过减弱GluN 2B活性诱导小鼠的躁狂样行为，这使得NMDAR拮抗剂能够避免情绪过度矫正。
Significance Although synaptotagmin-7 (Syt7) has been found to play an important role in bipolar-like behavioral abnormalities in mice, the molecular mechanisms underlying the aberrant behaviors remain unknown. The reason for the promising efficacy of N-methyl-d-aspartate receptor (NMDAR) antagonists, such as ketamine, in the treatment of bipolar depression is also unclear. In the present study, we demonstrated that in human induced pluripotent stem cell-derived and mouse hippocampal neurons, Syt7 triggered glutamate release in the peripheral active zone, which efficiently activated juxtaposed postsynaptic GluN2B-NMDARs. As a result of the Syt7 deficits, GluN2B-NMDARs became hypoactive and consequently generated antidepressant effects, which induced mania-like behavioral abnormalities in the animals. 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, N-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.
登录
查看更多内容
影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
Synaptotagmin 7充当CA2+传感器，用于突触囊泡补充。
影响因子：
7.7
作者：
Liu H;Bai H;Hui E;Yang L;Evans CS;Wang Z;Kwon SE;Chapman ER
通讯作者：
Chapman ER
影响因子：
8.2
作者：
Jordi León-Caballero;Isabella Pacchiarotti;A. Murru;M. Valentí;F. Colom;B. Benach;Víctor Pérez;Josep Dalmau;E. Vieta
通讯作者：
Jordi León-Caballero;Isabella Pacchiarotti;A. Murru;M. Valentí;F. Colom;B. Benach;Víctor Pérez;Josep Dalmau;E. Vieta
DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
DOI：
10.1016/j.dsx.2015.04.004
发表时间：
2015-07
期刊：
Diabetes & metabolic syndrome
影响因子：
--
作者：
A. Wysokiński;D. Strzelecki;I. Kloszewska
通讯作者：
A. Wysokiński;D. Strzelecki;I. Kloszewska