Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice.
Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice.
复制标题
DOI：
10.1523/jneurosci.6107-11.2012
复制
发表时间：
2012-05-09
期刊：
影响因子：
--
通讯作者：
Crawley JN
中科院分区：
文献类型：
--
作者：
Yang M;Bozdagi O;Scattoni ML;Wöhr M;Roullet FI;Katz AM;Abrams DN;Kalikhman D;Simon H;Woldeyohannes L;Zhang JY;Harris MJ;Saxena R;Silverman JL;Buxbaum JD;Crawley JN
突触支架蛋白基因SHANK3的突变与自闭症和McDermid 22q13缺失综合征密切相关。Shank3基因中突变的精确位置是其表型结果的关键。在这里，我们报告的生理和行为后果的空和杂合突变锚蛋白重复结构域在Shank3小鼠。纯合子和杂合子小鼠均表现出海马体中海马体能传递和长时程增强的减少，在纯合子小鼠中检测到更严重的缺陷。三个独立的队列进行了评估的幅度和可复制性的行为内表型相关的自闭症和McDermid综合征。轻微的社会障碍，主要是在青少年在相互作用，而所有的基因型显示正常的成年社交的三腔任务。受损的新物体识别和转棒性能是一致的空突变体的队列。重复的自我梳理，减少超声波发声，和赤字的逆转水迷宫学习只在一些队列中检测到，强调复制分析的重要性。这些结果表明，在确定症状的严重程度的Shank3基因内的离散域的缺失的精致的特异性。
Mutations in the synaptic scaffolding protein gene SHANK3 are strongly implicated in autism and Phelan-McDermid 22q13 deletion syndrome. The precise location of the mutation within the Shank3 gene is key to its phenotypic outcomes. Here we report the physiological and behavioral consequences of null and heterozygous mutations in the ankyrin repeat domain in Shank3 mice. Both homozygous and heterozygous mice showed reduced glutamatergic transmission and long-term potentiation in the hippocampus with more severe deficits detected in the homozygous mice. Three independent cohorts were evaluated for magnitude and replicability of behavioral endophenotypes relevant to autism and Phelan-McDermid syndrome. Mild social impairments were detected, primarily in juveniles during reciprocal interactions, while all genotypes displayed normal adult sociability on the three-chambered task. Impaired novel object recognition and rotarod performance were consistent across cohorts of null mutants. Repetitive self-grooming, reduced ultrasonic vocalizations, and deficits in reversal of water maze learning were detected only in some cohorts, emphasizing the importance of replication analyses. These results demonstrate the exquisite specificity of deletions in discrete domains within the Shank3 gene in determining severity of symptoms.