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

Nat Med. 2011 May;17(5):559-65. doi: 10.1038/nm.2336. Epub 2011 Apr 24.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult Stem Cells / physiology
  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Disease Models, Animal
  • Female
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / physiology*
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / pathology
  • Fragile X Syndrome / physiopathology*
  • Fragile X Syndrome / psychology
  • Hippocampus / pathology
  • Hippocampus / physiopathology*
  • Humans
  • Learning / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neural Stem Cells / physiology
  • Neurogenesis / genetics
  • Neurogenesis / physiology

Substances

  • FMR1 protein, human
  • Fmr1 protein, mouse
  • Fragile X Mental Retardation Protein