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, how FMRP deficiency contributes to the cognitive deficits in FXS is unclear. We have previously shown that Fmrp-null mice exhibit reduced adult hippocampal neurogenesis. Since Fmrp is also enriched in mature neurons, we explored the functional significance of Fmrp expression in neural stem and progenitor cells (aNSCs) and its role in adult neurogenesis. Here we show ablation of Fmrp in aNSCs via inducible gene recombination leads to reduced hippocampal neurogenesis in vitro and in vivo, as well as significantly impaired hippocampus-dependent learning in mice. Conversely, restoration of Fmrp expression specifically in aNSCs rescues these learning deficits. 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.

Reduced Adult Hippocampal Neurogenesis and Working Memory Deficits in theDgcr8-Deficient Mouse Model of 22q11.2 Deletion-Associated Schizophrenia Can Be Rescued by IGF2

“…Recently, Guo et al, 2011 clearly demonstrated the functional significance of adult neurogenesis using adult nestin-expressing precursor cell-specific conditional deletion of the fragile X mental retardation protein (Fmrp; responsible for fragile X syndrome) in mice. Moreover, disrupted in schizophrenia 1 (DISC1; a protein implicated in major mental disorders) was shown to promote proliferation of neural progenitors through the GSK3␤/␤-catenin pathway, and GSK3␤ inhibitor rescued the proliferation and behavior defect caused by DISC1 knockdown in adult mice (Mao et al, 2009).…”

“…Interestingly, we identified several genes in this group that had been shown previously to be downregulated in schizophrenia patients. For example, TTR has been reported recently to be significantly decreased in the CSF of schizophrenia patients (Huang et al, 2006). HTR2C and SULF1 have been demonstrated to be decreased in schizophrenic prefrontal cortex (Castensson et al, 2005;Narayan et al, 2008), and another group reported that the expression of Ace was decreased in their brains (Arregui et al, 1979).…”

“…Moreover, defective adult neurogenesis in the hippocampus has been suggested to be involved in learning impairment and the pathophysiology of some psychiatric and neurological disorders, such as schizophrenia and fragile X syndrome (Reif et al, 2006;Mao et al, 2009;Guo et al, 2011). However, despite the fact that a number of neurological disease risk genes have been shown to regulate adult neurogenesis, little is known about the properties of adult neurogenesis in animal models of psychiatric and neurological disorders, and their molecular pathogenesis remains unclear.…”

Serotonin dysregulation in Fragile X Syndrome: implications for treatment

“…However, by age 3-4 months, BDNF expression in the murine hippocampus is reduced compared to WT (52,55). Defects in hippocampal neurogenesis lead to cognitive deficits in the adult Fmr1 KO (56) and correlates with the hippocampal neurogenesis defects observed in individuals with FXS (57).…”

High-Throughput Screening to Identify Compounds That Increase Fragile X Mental Retardation Protein Expression in Neural Stem Cells Differentiated From Fragile X Syndrome Patient-Derived Induced Pluripotent Stem Cells

“…In addition, patients who exhibit mosaicism of either the CGG repeat size or DNA methylation levels on the FMR1 gene are able to make some FMRP and present with milder clinical symptoms [18]. Furthermore, restoring FMRP expression specifically in adult neural stem cells (NSCs) rescues hippocampus-dependent learning deficits in FMRP-deficient KO mice [19]. These observations suggest that partialrestoration ofFMRP even after birth could be clinically beneficial for patients with FXS.…”