title: Leptin induces hippocampal synaptogenesis via CREB-regulated microRNA-132 suppression of p250GAP.
abstract: Leptin acts in the hippocampus to enhance cognition and reduce depression and anxiety. Cognitive and emotional disorders are associated with abnormal hippocampal dendritic spine formation and synaptogenesis. Although leptin has been shown to induce synaptogenesis in the hypothalamus, its effects on hippocampal synaptogenesis and the mechanism(s) involved are not well understood. Here we show that leptin receptors (LepRs) are critical for hippocampal dendritic spine formation in vivo because db/db mice lacking the long form of the leptin receptor (LepRb) have reduced spine density on CA1 and CA3 neurons. Leptin promotes the formation of mature spines and functional glutamate synapses on hippocampal pyramidal neurons in both dissociated and slice cultures. These effects are blocked by short hairpin RNAs specifically targeting the LepRb and are absent in cultures from db/db mice. Activation of the LepR leads to cAMP response element-binding protein (CREB) phosphorylation and initiation of CREB-dependent transcription via the MAPK kinase/Erk pathway. Furthermore, both Mek/Erk and CREB activation are required for leptin-induced synaptogenesis. Leptin also increases expression of microRNA-132 (miR132), a well-known CREB target, which is also required for leptin-induced synaptogenesis. Last, leptin suppresses the expression of p250GAP, a miR132 target, and this suppression is obligatory for leptin's effects as is the downstream target of p250GAP, Rac1. LepRs appear to be critical in vivo as db/db mice have lowered hippocampal miR132 levels and elevated p250GAP expression. In conclusion, we identify a novel signaling pathway by which leptin increases synaptogenesis through inducing CREB transcription and increasing microRNA-mediated suppression of p250GAP activity, thus removing a known inhibitor of Rac1-stimulated synaptogenesis.
authors.affiliation: Department of Integrative Physiology and Neuroscience (M.D., M.Z., T.J.L., T.B., I.N.K., S.M.A., G.A.W.), Program in Neuroscience, Washington State University, Pullman, Washington 99164; Oregon Stem Cell Center (S.I.), Oregon Health and Sciences University, Portland, Oregon 97239; and Department of Neurophysiology (T.N.), Graduate School of Medicine, University of Tokyo, Tokyo 113-0033 Japan.
authors.forename: Matasha
authors.initials: M
authors.lastname: Dhar
authors.forename: Mingyan
authors.initials: M
authors.lastname: Zhu
authors.forename: Soren
authors.initials: S
authors.lastname: Impey
authors.forename: Talley J
authors.initials: TJ
authors.lastname: Lambert
authors.forename: Tyler
authors.initials: T
authors.lastname: Bland
authors.forename: Ilia N
authors.initials: IN
authors.lastname: Karatsoreos
authors.forename: Takanobu
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Appleyard
authors.forename: Gary A
authors.initials: GA
authors.lastname: Wayman
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000473:pathology / Q000502:physiology; D056654:CA3 Region, Hippocampal / Q000473:pathology / Q000502:physiology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D020738:Leptin / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009924:Organ Culture Techniques; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D054411:Receptors, Leptin / Q000235:genetics; D013569:Synapses / Q000502:physiology; D014158:Transcription, Genetic; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis* / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D020690:GTPase-Activating Proteins; D020738:Leptin; C546976:MIRN132 microRNA, mouse; D035683:MicroRNAs; D054411:Receptors, Leptin; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins