دورية
Intracisternal Gtf2iGene Therapy Ameliorates Deficits in Cognition and Synaptic Plasticity of a Mouse Model of Williams–Beuren Syndrome
| العنوان: | Intracisternal Gtf2iGene Therapy Ameliorates Deficits in Cognition and Synaptic Plasticity of a Mouse Model of Williams–Beuren Syndrome |
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| المؤلفون: | Borralleras, Cristina, Sahun, Ignasi, Pérez-Jurado, Luis A, Campuzano, Victoria |
| المصدر: | Molecular Therapy; November 2015, Vol. 23 Issue: 11 p1691-1699, 9p |
| مستخلص: | Williams–Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a heterozygous deletion of 26–28 genes at chromosome band 7q11.23. Haploinsufficiency at GTF2Ihas been shown to play a major role in the neurobehavioral phenotype. By characterizing the neuronal architecture in four animal models with intragenic, partial, and complete deletions of the WBS critical interval (ΔGtf2i+/–, ΔGtf2i–/–, PD, and CD), we clarify the involvement of Gtf2iin neurocognitive features. All mutant mice showed hypersociability, impaired motor learning and coordination, and altered anxiety-like behavior. Dendritic length was decreased in the CA1 of ΔGtf2i+/–, ΔGtf2i–/–, and CD mice. Spine density was reduced, and spines were shorter in ΔGtf2i–/–, PD, and CD mice. Overexpression of Pik3r1and downregulation of Bdnfwere observed in ΔGtf2i+/–, PD, and CD mice. Intracisternal Gtf2i-gene therapy in CD mice using adeno-associated virus resulted in increased mGtf2iexpression and normalization of Bdnflevels, along with beneficial effects in motor coordination, sociability, and anxiety, despite no significant changes in neuronal architecture. Our findings further indicate that Gtf2ihaploinsufficiency plays an important role in the neurodevelopmental and cognitive abnormalities of WBS and that it is possible to rescue part of this neurocognitive phenotype by restoring Gtf2iexpression levels in specific brain areas. |
| قاعدة البيانات: | Supplemental Index |
Full Text Finder | تدمد: | 15250016 15250024 |
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| DOI: | 10.1038/mt.2015.130 |