PMID- 23300470 OWN - NLM STAT- MEDLINE DCOM- 20130509 LR - 20211021 IS - 1553-7404 (Electronic) IS - 1553-7390 (Print) IS - 1553-7390 (Linking) VI - 8 IP - 12 DP - 2012 TI - Excessive astrocyte-derived neurotrophin-3 contributes to the abnormal neuronal dendritic development in a mouse model of fragile X syndrome. PG - e1003172 LID - 10.1371/journal.pgen.1003172 [doi] LID - e1003172 AB - Fragile X syndrome (FXS) is a form of inherited mental retardation in humans that results from expansion of a CGG repeat in the Fmr1 gene. Recent studies suggest a role of astrocytes in neuronal development. However, the mechanisms involved in the regulation process of astrocytes from FXS remain unclear. In this study, we found that astrocytes derived from a Fragile X model, the Fmr1 knockout (KO) mouse which lacks FMRP expression, inhibited the proper elaboration of dendritic processes of neurons in vitro. Furthermore, astrocytic conditioned medium (ACM) from KO astrocytes inhibited proper dendritic growth of both wild-type (WT) and KO neurons. Inducing expression of FMRP by transfection of FMRP vectors in KO astrocytes restored dendritic morphology and levels of synaptic proteins. Further experiments revealed elevated levels of the neurotrophin-3 (NT-3) in KO ACM and the prefrontal cortex of Fmr1 KO mice. However, the levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) were normal. FMRP has multiple RNA-binding motifs and is involved in translational regulation. RNA-binding protein immunoprecipitation (RIP) showed the NT-3 mRNA interacted with FMRP in WT astrocytes. Addition of high concentrations of exogenous NT-3 to culture medium reduced the dendrites of neurons and synaptic protein levels, whereas these measures were ameliorated by neutralizing antibody to NT-3 or knockdown of NT-3 expression in KO astrocytes through short hairpin RNAs (shRNAs). Prefrontal cortex microinjection of WT astrocytes or NT-3 shRNA infected KO astrocytes rescued the deficit of trace fear memory in KO mice, concomitantly decreased the NT-3 levels in the prefrontal cortex. This study indicates that excessive NT-3 from astrocytes contributes to the abnormal neuronal dendritic development and that astrocytes could be a potential therapeutic target for FXS. FAU - Yang, Qi AU - Yang Q AD - Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China. FAU - Feng, Bin AU - Feng B FAU - Zhang, Kun AU - Zhang K FAU - Guo, Yan-yan AU - Guo YY FAU - Liu, Shui-bing AU - Liu SB FAU - Wu, Yu-mei AU - Wu YM FAU - Li, Xiao-qiang AU - Li XQ FAU - Zhao, Ming-gao AU - Zhao MG LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20121227 PL - United States TA - PLoS Genet JT - PLoS genetics JID - 101239074 RN - 0 (Culture Media, Conditioned) RN - 0 (Fmr1 protein, mouse) RN - 0 (Nerve Growth Factors) RN - 0 (RNA-Binding Proteins) RN - 0 (neurotropin 3, mouse) RN - 139135-51-6 (Fragile X Mental Retardation Protein) SB - IM MH - Animals MH - *Astrocytes/cytology/metabolism MH - Cells, Cultured MH - Culture Media, Conditioned MH - Dendrites/physiology MH - Disease Models, Animal MH - *Fragile X Mental Retardation Protein/genetics/metabolism MH - *Fragile X Syndrome/genetics/metabolism MH - Mice MH - Mice, Knockout MH - *Nerve Growth Factors/genetics/metabolism MH - Neurons/cytology/physiology MH - Protein Binding MH - RNA-Binding Proteins/genetics/metabolism PMC - PMC3531466 COIS- The authors have declared that no competing interests exist. EDAT- 2013/01/10 06:00 MHDA- 2013/05/10 06:00 PMCR- 2012/12/01 CRDT- 2013/01/10 06:00 PHST- 2012/06/09 00:00 [received] PHST- 2012/10/31 00:00 [accepted] PHST- 2013/01/10 06:00 [entrez] PHST- 2013/01/10 06:00 [pubmed] PHST- 2013/05/10 06:00 [medline] PHST- 2012/12/01 00:00 [pmc-release] AID - PGENETICS-D-12-01437 [pii] AID - 10.1371/journal.pgen.1003172 [doi] PST - ppublish SO - PLoS Genet. 2012;8(12):e1003172. doi: 10.1371/journal.pgen.1003172. Epub 2012 Dec 27.