Intracisternal Gtf2i Gene Therapy Ameliorates Deficits in Cognition and Synaptic Plasticity of a Mouse Model of Williams-Beuren Syndrome
Intracisternal Gtf2i Gene Therapy Ameliorates Deficits in Cognition and Synaptic Plasticity of a Mouse Model of Williams-Beuren Syndrome
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DOI：
10.1038/mt.2015.130
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发表时间：
2015-11-01
影响因子：
12.4
通讯作者：
Campuzano, Victoria
中科院分区：
文献类型：
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作者：
Borralleras, Cristina;Sahun, Ignasi;Campuzano, Victoria
Williams-Beuren综合征（WBS）是由染色体7q11.23带26-28个基因的杂合缺失引起的神经发育障碍。GTF 2 I的单倍不足已被证明在神经行为表型中起主要作用。通过表征基因内、部分和完全缺失WBS关键间隔（Delta Gtf 2 i（+/-）、Delta Gtf 2 i（-/-）、PD和CD）的四种动物模型中的神经元结构，我们阐明了Gtf 2 i参与神经认知功能。所有突变小鼠都表现出过度社交，运动学习和协调能力受损，焦虑样行为改变。Delta Gtf 2 i（+/-）、Delta Gtf 2 i（-/-）和CD小鼠的CA 1中树突长度减少。在Delta Gtf 2 i（-/-）、PD和CD小鼠中，棘密度降低，并且棘较短。在Delta Gtf 2 i（+/-）、PD和CD小鼠中观察到Pik 3r 1的过表达和BDNF的下调。使用腺相关病毒对CD小鼠进行脑池内Gtf 2 i基因治疗，可增加mGtf 2 i表达，并使BDNF水平正常化，沿着对运动协调、社交和焦虑的有益作用，尽管神经元结构无显著变化。我们的研究结果进一步表明，Gtf 2 i单倍不足在WBS的神经发育和认知异常中起着重要作用，并且有可能通过恢复特定脑区Gtf 2 i表达水平来挽救这种神经认知表型的一部分。
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 (Delta Gtf2i(+/-), Delta Gtf2i(-/-), 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 Delta Gtf2i(+/-), Delta Gtf2i(-/-), and CD mice. Spine density was reduced, and spines were shorter in Delta Gtf2i(-/-), PD, and CD mice. Overexpression of Pik3r1 and downregulation of Bdnf were observed in Delta Gtf2i(+/-), 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.