Leptin Controls Glutamatergic Synaptogenesis and NMDA-Receptor Trafficking via Fyn Kinase Regulation of NR2B
Leptin Controls Glutamatergic Synaptogenesis and NMDA-Receptor Trafficking via Fyn Kinase Regulation of NR2B
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DOI：
10.1210/endocr/bqz030
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发表时间：
2020-02-01
期刊：
影响因子：
4.8
通讯作者：
Wayman, Gary A.
中科院分区：
文献类型：
--
作者：
Bland, Tyler;Zhu, Mingyan;Wayman, Gary A.
脂肪细胞因子/神经营养因子瘦素在中枢神经系统中激活瘦素受体LepRb具有促认知和抗抑郁作用。瘦素已被证明可以增加多个大脑区域中的多巴胺能突触发生。相比之下，LepRb基因突变的小鼠在海马体中显示出异常的突触发育，以及认知缺陷和抑郁样症状增加。瘦素增加谷氨酸能突触发生，部分是通过增强N-甲基-D-天冬氨酸（NMDA）受体功能来实现的;但潜在的信号通路尚不清楚。在这项研究中，我们研究如何瘦素调节海马神经元表面表达的NR 2B-含有NMDA受体。瘦素刺激增加NR 2B（Y1472）磷酸化，其被Src家族激酶抑制剂PP 1抑制。此外，我们表明，Fyn，Src家族激酶的成员，是必需的瘦素刺激NR 2B（Y1472）磷酸化。此外，用显性负性Fyn突变体或缺乏磷酸化位点的NR 2B突变体（NR 2B（Y1472 F））抑制Y1472磷酸化阻断瘦素刺激的突触发生。此外，我们表明，LepRb形成一个复杂的NR 2B和Fyn。总之，这些发现扩展了我们对LepRb相互作用组和瘦素刺激发育中海马神经元突触发生的机制的认识。理解这些机制是理解树突棘发育和突触发生的关键，树突棘发育和突触发生的改变与许多神经系统疾病有关。
Activation of the leptin receptor, LepRb, by the adipocytokine/neurotrophic factor leptin in the central nervous system has procognitive and antidepressive effects. Leptin has been shown to increase glutamatergic synaptogenesis in multiple brain regions. In contrast, mice that have a mutation in the LepRb gene show abnormal synapse development in the hippocampus as well as deficits in cognition and increased depressive-like symptoms. Leptin increases glutamatergic synaptogenesis, in part, through enhancement of N-methyl-D-aspartic acid (NMDA) receptor function; yet the underlying signaling pathway is not known. In this study, we examine how leptin regulates surface expression of NR2B-containing NMDA receptors in hippocampal neurons. Leptin stimulation increases NR2B(Y1472) phosphorylation, which is inhibited by the Src family kinase inhibitor, PP1. Moreover, we show that Fyn, a member of the Src family kinases, is required for leptin-stimulated NR2B(Y1472) phosphorylation. Furthermore, inhibiting Y1472 phosphorylation with either a dominant negative Fyn mutant or an NR2B mutant that lacks the phosphorylation site (NR2B(Y1472F)) blocks leptin-stimulated synaptogenesis. Additionally, we show that LepRb forms a complex with NR2B and Fyn. Taken together, these findings expand our knowledge of the LepRb interactome and the mechanisms by which leptin stimulates glutamatergic synaptogenesis in the developing hippocampus. Comprehending these mechanisms is key for understanding dendritic spine development and synaptogenesis, alterations of which are associated with many neurological disorders.