학술논문
Leptin Controls Glutamatergic Synaptogenesis and NMDA-Receptor Trafficking via Fyn Kinase Regulation of NR2B
RESEARCH ARTICLE
RESEARCH ARTICLE
Document Type
Report
Author
Source
Endocrinology. February 2020, Vol. 161 Issue 2, p1r, 14 p.
Subject
Language
English
ISSN
0013-7227
Abstract
Mutations in either the hormone leptin (obese, ob/ob) or the long form of its receptor (LepRb, diabetes, db/db) cause a large increase in food intake and morbid obesity in mice [...]
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.sup.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.sup.Y1472] phosphorylation. Furthermore, inhibiting Y1472 phosphorylation with either a dominant negative Fyn mutant or an NR2B mutant that lacks the phosphorylation site ([NR2B.sup.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. (Endocrinology 161: 1-14, 2020) Key Words: Leptin, NMDA receptor, synaptogenesis, receptor trafficking, hippocampus
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.sup.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.sup.Y1472] phosphorylation. Furthermore, inhibiting Y1472 phosphorylation with either a dominant negative Fyn mutant or an NR2B mutant that lacks the phosphorylation site ([NR2B.sup.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. (Endocrinology 161: 1-14, 2020) Key Words: Leptin, NMDA receptor, synaptogenesis, receptor trafficking, hippocampus