Journal
HIPPOCAMPUS
Volume 25, Issue 3, Pages 373-384Publisher
WILEY
DOI: 10.1002/hipo.22379
Keywords
geranylgeranyltransferase I; learning; memory; spine; Rac
Categories
Funding
- National Natural Science Foundation of China [81372699, 81272777, 31400930]
- Natural Science Foundation of Jiangsu province [BK2011195, BK20140217]
- Program for New Century Excellent Talents in University [NCET-10-0181]
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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. (c) 2014 Wiley Periodicals, Inc.
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