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Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning

Abstract

Deficiency in fragile X mental retardation protein (FMRP) results in fragile X syndrome (FXS), an inherited form of intellectual disability. Despite extensive research, it is unclear how FMRP deficiency contributes to the cognitive deficits in FXS. Fmrp-null mice show reduced adult hippocampal neurogenesis. As Fmrp is also enriched in mature neurons, we investigated the function of Fmrp expression in neural stem and progenitor cells (aNSCs) and its role in adult neurogenesis. Here we show that ablation of Fmrp in aNSCs by inducible gene recombination leads to reduced hippocampal neurogenesis in vitro and in vivo, as well as markedly impairing hippocampus-dependent learning in mice. Conversely, restoration of Fmrp expression specifically in aNSCs rescues these learning deficits in Fmrp-deficient mice. These data suggest that defective adult neurogenesis may contribute to the learning impairment seen in FXS, and these learning deficits can be rectified by delayed restoration of Fmrp specifically in aNSCs.

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Figure 1: Fmrp deletion in Nestin-expressing cells resulted in fewer YFP+ cells in the dentate gyrus.
Figure 2: Selective deletion of Fmrp in nestin-expressing cells alters cell proliferation and fate specification of aNSCs.
Figure 3: Selective deletion of Fmrp in primary aNSCs isolated from adult dentate gyrus results in altered proliferation and differentiation of aNSCs and reduced neurite extension of aNSC-differentiated neurons.
Figure 4: Deletion of Fmrp from Nestin-positive aNSCs results in deficits in hippocampus-dependent learning.
Figure 5: Restoration of Fmrp in primary aNSCs rescues proliferation and differentiation deficits of Fmrp-deficient aNSCs and neurite extension deficits of aNSC-differentiated neurons.
Figure 6: Restoration of Fmrp in Nestin-expressing aNSCs and their progeny rescues hippocampus-dependent learning deficits in Fmrp-deficient mice.

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Acknowledgements

We thank C.T. Strauss for editing the manuscript; H. van Praag, D. Schaffer and T. Xie for critical reading of the manuscript; members of the Zhao lab for discussions; S.J. von Hoyningen-Huene for technical assistance; D.C. Lagace and R.D. Smrt for technical help; and H. van Praag (US National Institutes of Health (NIH)/National Institute of Aging) and F. Gage (Salk Institute) for the Cre-GFP construct. This work was supported by grants from the NIH to X.Z. (MH080434 and MH078972) and D.L.N. (HD38038 and HD024064). E.G.S. is supported by an NIH National Institute of Mental Health Career Opportunity for Research training grant (MH19101). Images in this paper were generated in the University of New Mexico Cancer Center Fluorescence Microscopy Shared Resource, funded as detailed here: http://hsc.unm.edu/crtc/microscopy/acknowledgement.shtml/.

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W.G. and X.Z. planned the experiments, analyzed data and wrote the manuscript. A.M.A. developed, carried out and analyzed data for behavioral analyses. W.G., L.Z., E.B.J., E.G.S., A.C.M., S.L.G. and A.M.A. carried out all the experiments. P.J. helped with mouse line acquisition and concept development. R.Z., B.A.O. and D.L.N. made Fmr1-cON mice. A.J.E. provided the Nes-CreERT2 and ROSA26-YFP mouse lines and guided histological analysis.

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Correspondence to Xinyu Zhao.

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Guo, W., Allan, A., Zong, R. et al. Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning. Nat Med 17, 559–565 (2011). https://doi.org/10.1038/nm.2336

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