Intracisternal Gtf2i Gene Therapy Ameliorates Deficits in Cognition and Synaptic Plasticity of a Mouse Model of Williams-Beuren Syndrome.

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a heterozygous deletion of 26-28 genes at chromosome band 7q11.23. Haploinsufficiency at GTF2I has 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 Gtf2i in 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 Pik3r1 and downregulation of Bdnf were observed in ΔGtf2i(+/-), PD, and CD mice. Intracisternal Gtf2i-gene therapy in CD mice using adeno-associated virus resulted in increased mGtf2i expression and normalization of Bdnf levels, along with beneficial effects in motor coordination, sociability, and anxiety, despite no significant changes in neuronal architecture. Our findings further indicate that Gtf2i haploinsufficiency 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 Gtf2i expression levels in specific brain areas.