Abstract
Background Fragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic form of autism, is caused by a loss of FMRP translational regulator 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects.
Methods We treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying persistent effects of Nutlin-3, we analyzed proliferation and differentiation of neural stem cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice.
Results We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6-month of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to extracellular matrix, secreted factors, and cell membrane proteins in FMR1-deficient hippocampus.
Conclusions Our data indicates that transient Nutlin-3 treatment in young adults leads to long-lasting neurogenic and behavioral changes through modulating adult neurogenic niche rather than intrinsic properties of adult neural stem cells. Our results demonstrate that cognitive impairments in FXS may be prevented by an early intervention through Nutlin-3 treatment.
Competing Interest Statement
X.Z. and Y.L. are inventors of a patent (METHODS FOR TREATING COGNITIVE DEFICITS ASSOCIATED WITH FRAGILE X SYNDROME, United States US 9,962,380 B2). The remaining authors declare no competing interests.
Abbreviations
- ASD
- autism spectrum disorder
- ANOVA
- Analysis of variance
- BrdU
- Bromodeoxyuridine
- cKO
- Conditional knockout
- DEG
- Differentially expressed gene
- CE
- Coefficient of error
- DG
- Dentate gyrus
- ECM
- Extracellular matrix
- Erdr1
- Erythroid differentiation regulator 1
- Fig
- Figure
- Fmr1
- Fragile x mental retardation protein 1
- FMR1
- Translational regulator 1 (official name)
- FMRP
- Fragile x mental retardation protein (previous name)
- FXS
- Fragile x syndrome
- GAPDH
- Glyceraldehyde-3-phosphate dehydrogenase
- GC
- Granule cell
- GFP
- Green fluorescent protein
- GFAP
- Glial fibrillary acidic protein
- GO
- Gene ontology
- HDAC1
- Histone deacetylase 1
- KO
- Knockout
- qPCR
- quantitative polymerase chain reaction
- MCM2
- Minichromosome maintenance complex component 2
- MDM2
- mouse double minute 2
- NeuN
- Neuronal nuclei antigen
- NIH
- National institute of health
- NLR
- Novel location recognition
- NOR
- Novel object recognition
- NSPC
- Neural stem/progenitor cell
- NSC
- Neural stem cell
- NP
- Neural progenitors
- Nut3
- Nutlin3
- p53
- Protein
- PFA
- Paraformaldehyde
- RBFOX3
- RNA binding fox-1 homolog 3
- RGL
- Radial glial like
- SGZ
- Subgranular zone
- SVZ
- Subventricular zone
- TF
- Transcription factor
- Veh
- Vehicle
- WT
- Wild type