Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide repeat expansion in the FMR1 gene that codes for fragile X mental retardation protein (FMRP). To determine if FMRP expression in the central nervous system could reverse phenotypic deficits in the Fmr1 knockout (KO) mouse model of FXS, we used a single-stranded adeno-associated viral (AAV) vector with viral capsids from serotype 9 that contained a major isoform of FMRP. FMRP transgene expression was driven by the neuron-selective synapsin-1 promoter. The vector was delivered to the brain via a single bilateral intracerebroventricular injection into neonatal Fmr1 KO mice and transgene expression and behavioral assessments were conducted 22-26 or 50-56 days post injection. Western blotting and immunocytochemical analyses of AAV-FMRP-injected mice revealed FMRP expression in the striatum, hippocampus, retrosplenial cortex, and cingulate cortex. Cellular expression was selective for neurons and reached ∼ 50% of wild-type levels in the hippocampus and cortex at 56 days post injection. The pathologically elevated repetitive behavior and the deficit in social dominance behavior seen in phosphate-buffered saline-injected Fmr1 KO mice were reversed in AAV-FMRP-injected mice. These results provide the first proof of principle that gene therapy can correct specific behavioral abnormalities in the mouse model of FXS.
CITATION STYLE
Gholizadeh, S., Arsenault, J., Xuan, I. C. ong Y., Pacey, L. K., & Hampson, D. R. (2014). Reduced phenotypic severity following adeno-associated virus-mediated Fmr1 gene delivery in fragile X mice. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 39(13), 3100–3111. https://doi.org/10.1038/npp.2014.167
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