title: Inhibiting geranylgeranyltransferase I activity decreases spine density in central nervous system.
abstract: Geranylgeranyltransferase I (GGT), a protein prenyltransferase, is responsible for the posttranslational lipidation of Rho GTPases, such as Rac, Rho and Cdc42, all of which play an important role in neuronal synaptogenesis. We previously demonstrated that GGT promotes dendritic morphogenesis in cultured hippocampal neurons and cerebellar slices. We report here that inhibiting GGT activity decreases basal- and activity-dependent changes in spine density as well as in learning and memory ability of mice in vivo. We found that KCl- or bicuculline-induced dendritic spine density increases was abolished by specific GGT inhibitor GGTi-2147 treatment in cultured hippocampal neurons. GGTi-2147 lateral ventricular injection reduced GGT activity and membrane association of Rac and decreased the density of dendritic spines in the mouse hippocampus, frontal cortex and cerebellum. GGTi-2147 administration also impaired learning and memory ability of mice. More importantly, mice exposed to environmental enrichment (EE) showed increased spine density and learning and memory ability, which were significantly reversed by GGTi-2147 administration. These data demonstrate that inhibiting GGT activity prevents both basal- and activity-dependent changes in spine density in central nervous system both in vitro and in vivo. Manipulating GGT activity may be a promising strategy for the therapies of neurodevelopmental disorders, such as autism, depression, and schizophrenia.
authors.affiliation: The Graduate School, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Maochun
authors.initials: M
authors.lastname: Yuan
authors.forename: Shangfeng
authors.initials: S
authors.lastname: Gao
authors.forename: Chengdong
authors.initials: C
authors.lastname: Sun
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shi
authors.forename: Jinxia
authors.initials: J
authors.lastname: Hu
authors.forename: Rutong
authors.initials: R
authors.lastname: Yu
authors.forename: Xiuping
authors.initials: X
authors.lastname: Zhou
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007093:Imidazoles / Q000494:pharmacology; D007858:Learning / Q000187:drug effects; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D058787:GABA-A Receptor Antagonists; C466792:GGTI 2147; D007093:Imidazoles; D011189:Potassium Chloride; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D020744:rac GTP-Binding Proteins; D007930:Leucine; D001640:Bicuculline
keywords: Rac; geranylgeranyltransferase I; learning; memory; spine